CENTERS FOR DISEASE CONTROL AND PREVENTION 

NATIONAL IMMUNIZATION PROGRAM 

RECORD OF THE MEETING OF THE 

ADVISORY COMMITTEE ON IMMUNIZATION 

PRACTICES 

February 21-22, 2006 

Meeting held at the Centers for Disease Control and Prevention 

Atlanta, Georgia 

This document has been archived for historical purposes.
Acronyms Used In This Report

AAFP American Academy of Family Practitioners 

AAP American Academy of Pediatrics 

ACHA American College Health Association 

ACIP Advisory Committee on Immunization Practices

ACOG American College of Obstetrics and Gynecology 

AE (SAE) Adverse Event (Seriours AE) 

AIS Adenocarcinoma In-Situ

AMA American Medical Association

ASC American Society for Colposcopy 

ASCCP American Society for Colposcopy and Cervical Pathology 

ASCUS Atypical Squamous Cells Of Undetermined Significance

CB® Cost Benefit (Ratio) 

BRFSS Behavioral Risk Factor Surveillance Survey 

CAP Condom-Availability Programs

CDC Centers for Disease Control and Prevention 

CER Cost Effectiveness Ratio 

CI Confidence Interval

CIN Cervical Intraepithelial Neoplasia

D&C Dilation and Curettage

DCPC Division of Cancer Prevention and Control 

DHHS Department of Health and Human Services

DSMB Data Safety Monitoring Board

DSTD Division of STD Prevention 

DTaP Diphtheria, Tetanus, Acellular Pertussis (vaccine)

ED Emergency Department

ELISA Enzyme-Linked Immunosorbent Assay 

FDA Food and Drug Administration 

FRC Famiy Research Council

GMC Granulocyte Macrophage Colony 

GMT Geometric Mean Titer 

GSK GlaxoSmithKline

HIV/AIDS Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome 

HPV Human Papilloma Virus

HSIL High-Grade Squamous Intraepithelial Lesions

HZ Herpes Zoster

ID Intradermal

IDSA Infectious Disease Society of America

Ig Immune Globulin (IgA, class A, IgG, class G)

IGIV Intravenous Immune Globulin

IM Intramuscular

IND Investigational New Drug

IPV Injected Polio Vaccine 

LAIV Live Attentuated Influenza Vaccine

MMR(V) Measles, Mumps, Rubella (Varicella) vaccine

MPSV Meningococcal Polysaccharide Vaccine

NACCHO National Association of County and City Health Officials 

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NCHS National Center for Health Statistics

NCI National Cancer Institute

NCID National Center for Infectious Diseases

NFID National Foundation of Infectious Diseases 

NHANES National Health and Nutritional Examination Survey 

NHIS National Health Interview Survey 

NIH National Institutes of Health

NIP National Immunization Program 

NSFG National Survey of Family Growth

NVPO National Vaccine Program Office

NVSN National Vaccine Surveillance Network

OPV Oral Polio Vaccine

PAP Papanicolau (cancer test)

PHN Post-Herpetic Neuralgia

PPD/TST Purified Protein Derivative/Tuberculin Skin Test 

PRV Pentavalent Human Bovine Reassortant Rotavirus Vaccine 

QALY Quality Adjusted Life Year

REST Rotavirus Efficacy and Safety Trial

RFI Request for Information 

RRP Recurrent Respiratory Papillomatosis

RV Rotavirus 

SAM Society for Adolescent Medicine

SEER Surveillance, Epidemiology and End Results 

SES Socioeconomic Status 

SNS Strategic National Stockpile

SPS Shingles Prevention Study 

STD Sexually Transmitted Disease

VAERS Vaccine Adverse Event Reporting System 

VE Vaccine Efficacy 

VFC Vaccines for Children (Program)

VLP Virus-Like Particles 

VSD Vaccine Safety Datalink

VZV Varicella Zoster Virus

VZIG Varicella Zoster Immune Globulin

WHO World Health Organization 

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Table of Contents 

Acronyms Used In This Report .................................................................................................... a

OCTOBER 26, 2005...................................................................................................................... 5

OPENING COMMENTS ......................................................................................................... 5

HUMAN PAPILLOMAVIRUS VACCINE ........................................................................... 6

Background ............................................................................................................................ 6

The Biology of HPV ............................................................................................................... 6

HPV Epidemiology in the U.S. .............................................................................................. 8

Cervical Cancer in the U.S. ................................................................................................. 10

GSK HPV Vaccine Clinical Trial Data ............................................................................... 12

GARDASIL® Presentation .................................................................................................. 15

Cost Effectiveness of HPV Vaccination .............................................................................. 22

Mathematical Modeling of HPV Vaccine ........................................................................... 25

Behavioral Issues Related to HPV Vaccination ................................................................. 27

Options for ACIP Recommendation on HPV Vaccine ....................................................... 28

PUBLIC COMMENT ............................................................................................................. 32

ROTAVIRUS VACCINE ........................................................................................................... 34

Data Review, Rotavirus Efficacy and Safety Trial (REST) .................................................... 34

Rotavirus Vaccine Working Group Draft Proposed Recommendations ........................... 42

Vote....................................................................................................................................... 44

VFC Resolution .................................................................................................................... 44

ACIP GENERAL RECOMMENDATIONS ON IMMUNIZATION ................................ 45

Revisions to the General Recommendations ........................................................................... 45

New Revisions to the General Recommendations since October 2005 .................................. 47

Public Comment .................................................................................................................. 50

FEBRUARY 22, 2006 ................................................................................................................. 50

CDC DIRECTOR’S COMMENTS ....................................................................................... 50

OLD BUSINESS...................................................................................................................... 52

Resolution to Add Rotavirus Vaccine to the VFC .............................................................. 52

Vote....................................................................................................................................... 53

Changes to the ACIP General Recommendation ............................................................... 53

Vote....................................................................................................................................... 54

VARICELLA ZOSTER IMMUNE GLOBULIN ................................................................ 55

VZIG Update: Availability of a New Product ..................................................................... 55

INFLUENZA VACCINE ....................................................................................................... 56

Introduction .......................................................................................................................... 56

Review of 2005 Influenza Vaccine Summit Meeting. ......................................................... 57

Presentation by National Foundation for Infectious Diseases .......................................... 58

Influenza Surveillance Data Update ................................................................................... 60

Key Issues/Changes Proposed for the 2006-07 Influenza Recommendations .................. 61

Vote....................................................................................................................................... 66

Recommended influenza vaccination for children aged 24-59 months ............................. 66

Vote....................................................................................................................................... 67

Vote....................................................................................................................................... 68

VFC Changes Relevant To Influenza Vaccine ................................................................... 68

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Vote....................................................................................................................................... 69

Update on HHS Pandemic Influenza Planning ................................................................. 69

NIH/NIAID H5N1 Update................................................................................................... 70

TETANUS-, DIPHTHERIA TOXOID, ACELLULAR PERTUSSIS VACCINES ......... 72

Report from the Pertussis Working Group ......................................................................... 72

Manufacturer Updates ......................................................................................................... 73

Tdap Use Among Adults Aged >65 Years ........................................................................... 74

Vote....................................................................................................................................... 78

Tdap Use Among Healthcare Workers ............................................................................... 78

Cost-Benefit Analysis of Tdap Vaccination of Health-Care Workers ............................... 80

Proposed Tdap Recommendations ...................................................................................... 82

Vote....................................................................................................................................... 85

HERPES ZOSTER (SHINGLES) VACCINE ..................................................................... 85

Storage/Handling of Herpes Zoster Vaccine ...................................................................... 85

Survey of Internists/Family Care Practitioners About Herpes Zoster Vaccine ................ 86

Shingles Prevention Trial, Zostavax® ................................................................................ 88

Public Comment. ................................................................................................................. 91

ACIP EVIDENCE BASED RECOMMENDATION CLASSIFICATIONS ..................... 91

Closing comments. .................................................................................................................. 94

Appendix: Attendance................................................................................ 95

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CENTERS FOR DISEASE CONTROL AND PREVENTION

NATIONAL IMMUNIZATION PROGRAM

ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES

MINUTES OF THE MEETING

FEBRUARY 21-22, 2006

OCTOBER 26, 2005 

A meeting of the Advisory Committee on Immunization Practices (ACIP) was convened by the 

Centers for Disease Control and Prevention’s (CDC) National Immunization Program (NIP) at 

the CDC Global Communications Center in Atlanta, Georgia, on February 21-22, 2006. This 

report is organized according to the meeting agenda, which was posted on CDC’s ACIP website

and distributed at the meeting. ACIP Chairman Dr. Jonathan Abramson convened the meeting at 

8:02 a.m., welcoming all in attendance (see Attachment #1).

OPENING COMMENTS 

ACIP Executive Secretary Dr. Larry Pickering made several announcements: 

• He welcomed the new NIP Director, Dr. Anne Schuchat; Dr. Robert Davis, director 

of the CDC Immunization Safety Office (ISO); and Dr. Jean Smith, Assistant to the 

NIP Director for Immunization Policy. 

• New liaisons present were Dr. Jeffrey Duchin, for the NACCHO.

• Dr. Renee Jenkins attended for Dr. Patricia Whitley-Williams (NMA), as did Dr. 

Mark Whitaker for Dr. Andrea Gelzer (AAHP). Dr. Charles Helms (NVAC) was 

absent.

• The ACIP home page is www.cdc.gov/nip/acip and the email address is 

acip@cdc.gov. 

• The remaining 2006 ACIP meeting dates are June 29-30 and October 25-26. 

• ACIP Protocol: A quorum of ACIP members must be maintained to conduct 

committee business. In the absence of a quorum (eight members) of members 

qualified to vote, the ACIP charter allows the Executive Secretary to temporarily 

designate ex officio members as voting members. If voting, the ex-officio members 

are asked to disclose any potential conflicts of interest. ACIP members with potential 

conflicts of interest are asked to disclose all vaccine-related work and financial 

interests, and to refrain from any discussion or vote that is related to such matters. 

When needed, however, limited waivers of such conflicts of interest can be granted to 

enable the members to provide their expertise to the Committee. Waivers may be 

issued, for example, to members who also conduct clinical vaccine trials, or who 

serve on a Data Safety Monitoring Board (DSMB). Those members may provide 

information to the committee and discuss other vaccines produced by the same 

company, but they may not participate in discussion on the vaccine involving their 

conflict, nor in any related votes. 

• Meeting time is reserved for public comment at scheduled intervals, but may also 

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occur during open discussion if time permits and the Chair recognizes a speaker. 

• Slide presentations from this meeting were posted on the ACIP website after the 

meeting. 

The members and liaisons then introduced themselves (see Attachment #1). Those reporting 

potential conflicts of interest were Mr. Beck (awaiting a decision from the Office of General 

Counsel about stock), Dr. Gilsdorf (uncompensated, independent safety monitor for an NIHsponsored vaccine trial, but not compensated); Dr. Harry Hull (discussing potential projects with 

MedImmune); Dr. Greg Poland (chairs a Merck DMSB, serves on the DVC scientific advisory 

board and has conducted clinical trials for Chiron, Merck, and Vaxgen); and Dr. John Treanor 

(conducting influenza vaccine clinical trials for Merck, GlaxoSmithKline (ID Biomedical); 

Protein Sciences Corporation, and conducting laboratory studies for AlphaVax). 

HUMAN PAPILLOMAVIRUS VACCINE

Background 

Dr. Janet Gilsdorf, HPV Working Group Chair

Overview: Summary of HPV vaccine Working Group activities

• The HPV vaccine Working Group was formed in February 2004; members include 

representatives from ACIP, FDA, NIH, NIP, DSTD, DCPC, NCID and 

Consultants/liaisons from AAP, AAFP, ACOG, SAM, IDSA, ACHA. There have 

been presentations from industry, academia and at least monthly conference calls to 

review trial data. 

• Two HPV vaccines are in development. Both vaccines have a three-dose schedule; 

GSK’s bivalent targets females and Merck’s quadrivalent targets both genders. Both 

companies outlined product development plans and initial data for ACIP in February 

2005 and Merck’s efficacy data were presented that October. 

• On this day, presentations addressed the background on HPV biology, epidemiology, 

and cervical cancer in the U.S.; preliminary efficacy, immunogenicity, and safety data 

for the GSK bivalent HPV vaccine; efficacy, immunogenicity, and safety data for the 

Merck quadrivalent HPV vaccine; modeling data on cost effectiveness/impact of 

HPV vaccine; HPV-related sexual behavior; and considerations regarding 

recommendations for use of the Merck HPV vaccine. 

The Biology of HPV 

Presenter: Dr. Doug Lowy, NCI 

Overview: HPV biology. Disclosure: Dr. Lowy is an inventor of the VLP vaccine 

technology that is patented by NIH and licensed to Merck and GlaxoSmithKline. 

Cervical cancer is the second most common cancer of women worldwide. It represents about 

10% of all cancers of women with ~70% of these cancers being caused by HPV-16 and HPV-18. 

HPV16 also causes other mucosal epithelial cancers. The HPV vaccines target HPV-16 and 

HPV-18. The Merck vaccine also targets HPV-6 and HPV-11, which cause most external genital 

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warts. Nongenital, common or flat warts are also caused by HPV, but by types other than those 

in the vaccines. 

The capsid of the HPV virion is composed of 360 copies of the L1 the major structural protein 

(arranged as 72 pentamers), and a smaller number of copies of L2, the minor structural protein. . 

L1 contains the immunodominant neutralization epitopes, which are conformation-dependent 

and predominantly type-specific. When L1 is expressed in cells, it is sufficient to form virus-like 

particles (VLPs) whose structure resembles authentic virion capsids. The L1 VLPs contain the 

neutralization epitopes, so that they induce high titers of neutralizing antibodies. When L1 and 

L2 are co-expressed in cells, they associate with each other and form L1/L2 VLPs. In studies 

with animal papillomaviruses, systemic immunization with L1 VLPs was highly protective 

against high-dose experimental viral challenge, and L1/L2 VLPs did not confer additional 

protection. Therefore, vaccine development has focused on L1 VLPs. The animal studies also 

showed that neutralizing antibodies are probably the main protective activity induced by the 

VLPs, since passive transfer of immune IgG is protective. The vaccine was active 

prophylactically, but not therapeutically against established lesions. Heterologous neutralizing 

antibodies were not protective, implying that the protective factor is type-specific. The 

neutralizing antibodies can work by interfering with the binding of the virus to the cell, with its 

cellular uptake upon binding, or with its uncoating inside the cell. 

HPVs infect stratified squamous (i.e., multilayered) epithelia. To establish a persistent infection, 

the virus must infect cells in the basal epithelial layer, which contains the epithelial stem cells 

and is the main source of dividing cells in this tissue. Access of the virus to the basal cells is 

believed to require microtrauma to the epithelium. Microtrauma in the genital area can lead to 

the acquisition of HPV infection through sexual intercourse with an infected partner. Chronic 

infection is established because the viral genome resides in the basal stem cells or in long-lived 

basal cells. 

Several factors may contribute to the ability of the neutralizing antibodies induced by the vaccine 

to protect against infection of the female genital tract. One is that IgG is the main 

immunoglobulin in the female genital tract, and neutralizing IgG antibodies, which are the main 

class induced by systemic immunization, are transudated into the female genital tract. Another is 

that the epithelial microtrauma that in the absence of neutralizing antibodies predisposes to 

infection may provide access to the systemic antibodies, thereby increasing the local 

concentration of neutralizing antibodies. 

The L1 VLP vaccines are unlikely to be directly therapeutic, particularly for the intermediate and 

high-grade dysplasias, as these lesions express little or no L1 protein. The vaccines might 

theoretically have some therapeutic activity for low-grade lesions, as they do express L1 protein. 

However, most of the L1 protein is in the upper layers of the epithelium, and resolution of the 

lesion would require that the L1 protein in the lesion produce a sufficiently robust reaction to 

destroy the basal cells that harbor the viral genome. It is more likely that the VLP vaccine may 

reduce HPV spread from an infected site to a previously uninfected site by neutralizing the virus 

that comes from a lesion. In summary, the L1 virion immunodominant epitopes are 

conformation-dependent. Preclinical studies indicate that vaccination with L1 VLPs induce 

neutralizing antibodies that are predominantly type-specific. Systemic immunization could 

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deliver these antibodies to sites of microtrauma from sexual intercourse. In addition to 

preventing new infection, an L1 VLP vaccine might reduce HPV spread, but it is not likely to 

treat established lesions, particularly moderate- or high-grade dysplasias.. 

HPV Epidemiology in the U.S.

Presenter: Dr. Eileen Dunne, DSTDP

Overview: HPV infection and disease burden of HPV-associated conditions in the 

U.S., principally among women; sexual transmission; laboratory diagnostic methods, 

treatment; issues of immunity and serology. 

The prevalence of HPV infection is high in both males and females. Of the >100 HPV types, 

approximately 60 types are cutaneous and cause the common skin wart. The 40 mucosal types 

are divided into high-risk types and low-risk types. High-risk HPV types are epidemiologically 

associated with cervical and other anogenital cancers. Of those, two of the most important are 

HPV-16 and HPV-18. The most common of the low-risk HPV types are HPV-6 and HPV-11. 

Multiple HPV types are often detected, but HPV-16 is the most common type, with a 10% 

cumulative incidence at two years after first sexual intercourse. HPV persistence is associated 

with increased risk of cervical cancer precursors and cervical cancer. Information on HPV 

infection among men is limited, but natural history studies are ongoing. There is limited utility 

for HPV serology as a marker of cumulative incidence because serological tests will 

underestimate past or current HPV infection. 

The HPV types associated with cervical cancer around the world were analyzed by Clifford et al 

(Br J Cancer, 2003) in a meta-analysis of studies evaluating cervical cancer biopsy samples for 

HPV types. Types 16 and 18 were consistently associated with >70% of cervical cancers 

worldwide. The conditions associated with HPV-16, -18, -6, and -11 were listed, indicating the 

potential benefit of a quadrivalent HPV vaccine. Other than cervical cancer, HPV-16 and -18 

also cause a high proportion (80%) of high- and low-grade cervical abnormalities; anal and 

anogenital cancers, and ~10% of head and neck cancers. The low-risk Types 6 and 11 cause 90% 

of genital warts and recurrent respiratory papillomatosis, as well as low -grade cervical 

abnormalities. 

Among HPV-6 and -11 associated conditions are genital warts and recurrent respiratory 

papillomatosis (RRP). The peak prevalence of genital warts appears to be at ages 20-29 years in 

both men and women; one study demonstrated the incidence rate at 157/100,000 persons. These 

warts recur in 30% of cases and cause multiple treatment visits. RRP is a condition in which 

warts grow in the respiratory tract, a rare but debilitating and recurrent disease that can require 

multiple surgeries. It is most common in juveniles and is most likely maternally transmitted. 

Estimated prevalence of juvenile-onset RRP is 1-4/ 00,000 children aged <18 years, and 

incidence is 0.1-2.1/100,000 children. A voluntary RRP registry indicates a median of 13 

lifetime surgeries, with a range of 2-179 surgeries. 

HPV acquisition occurs soon after sexual initiation, with most infections clearing quickly, but 

some persisting. The lifetime cumulative incidence is high, models have demonstrated >80% of 

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persons have had infection with HPV by age 50. Persistent infection is associated with high 

grade cervical intraepithelial neoplasias (CIN) which can lead to cervical cancer. Screening with 

the routine Pap tests can usually detect these early for treatment.

 

Transmission of HPV occurs primarily by sexual contact, usually sexual intercourse. However, 

other types of sexual contact can transmit HPV, but transmission occurs much less frequently. 

Transmission is determined by per partner transmission probability, infectiousness, and average 

number of partnerships formed per unit time. There is no epidemiologic data on HPV 

transmission probability per sex-act, or per partnership, however models estimate that 0.4 as a 

median probability of per-sex act transmission, and 0.6 as a probability of transmission perpartnership, in another. This would mean that transmission would likely occur by three sex acts. 

Sex, age, infection site, immune status, and HPV type may also contribute to risk of 

transmission. 

With regard to HPV laboratory methods, there is no culture for HPV, detection of DNA is used 

to measure infection. HPV DNA detection occurs by PCR or, in a cervical cancer screening and 

management clinical setting, by a hybridization assay (the Digene Hybrid Capture II). This HCII 

test detects 13 high-risk HPV types. Other tests available include HPV serology, which is an 

ELISA type-specific antibody serology (IgG or IgA) test to L1 VLPs. This test can test for 

serum or mucosal antibodies, and there is poor standardization of methods. 

There are certain challenges to describing the epidemiology of HPV infection in the U.S. There 

is no culture for HPV infection, detection of DNA is used to measure infection. Presence of 

HPV DNA does not necessarily indicate infectious virus. National incidence and surveillance 

data are very limited, as there is not routine testing for HPV infection, nor is there reporting of 

HPV infection or HPV-associated conditions. And, HPV infection or HPV-associated conditions 

are not always associated with antibody detection. 

• U.S. national HPV prevalence has been estimated at 20 million people or 15% of 

Americans aged 15-49 years. Estimated incidence is 6.2 million infections annually 

(>50% of sexually active men and women over their lifetime). 

• The 2002 National Survey of Family Growth and 2003 Youth Risk Behavioral Survey 

indicate that ~7% of young persons have had sex before age 13 years, 25% by age 15 

years, and 48% by 17 years. An estimated 14% of females and 18% of males aged 15-

19 years have had ≥2 sex partners in the last 12 months. 

• A review of HPV prevalence studies (Revzina NV. Int J STD/AIDS, 2005) showed 

high HPV DNA prevalence among U.S. women in all clinic settings (e.g., STD, 

family planning clinics). Not surprisingly, the highest prevalence was in STD clinics 

(49-90% of females had HPV infection). 

• A CDC cross-sectional analysis of HPV infection among women having a Pap test in 

six U.S. cities (N=5500, aged 14-65 years) from 2003 to 2004, found the highest 

prevalence (40%) of high-risk HPV infection among 14-19 year-olds. Prevalence of 

HPV infection decreased with older age. HPV prevalence by race/ethnicity was 

similar; somewhat lower among Asian women, but not significantly when ageadjusted. 

• The prevalence of HPV of any type was 26.9% among college women aged 18-25 

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years (N=3262), as determined by less sensitive urine methods (Manhart L, STD, in 

press). Prevalence of HPV ranged from 0.2-5.8% among types 6, 11, 16 and 18, with 

Type 16 being the most common. The same data analyzed by number of sex partners 

found 14% HPV prevalence in these women, even with one sex partner. This rose 

with increasing numbers of lifetime sex partners. 

• Winer et al (Am J Epidemiol,2003:157) followed young college women after sexual 

initiation, and found HPV was acquired soon after first sexual intercourse. Two years 

after first sexual intercourse, cumulative incidence of any HPV infection was 40%, 

and >50% four years later. At 2 years, type-specific cumulative incidence was 0.9-

10.4% percent,; the highest acquisition was for HPV-16. 

Persistent HPV is often defined as infection detected at more than one visit, usually at four to six 

months apart. That is an important predictor for high-grade cervical cancer precursors and 

invasive cervical cancer (10% by Schlecth et at, JAMA, 2001; and 14.1% by Moscicki et al, J 

Pediatr, 1998). Other risk factors have included HPV Type 16; immune status; smoking; 

multiple HPV-type infections; older age; and certain STDs, including chlamydia and herpes. 

Immune response to infection is important to clear infection, but the immune response to HPV 

remains unclear.

 

Data on type-specific HPV immunity are few, but some studies demonstrate few women later reacquire the same type of infection if that type has been cleared. This suggests short-term, typespecific immunity. There are no longitudinal cohort studies to assess immunity over a lifetime. 

Natural history studies have found no cross-protection between HPV types. 

HPV infection in men has been less studied, but the few existing studies demonstrate equal HPV 

prevalence to that of females, depending on the site and sample collected. Several ongoing 

longitudinal studies are assessing HPV clearance and persistence, and the development of HPVassociated conditions among men. Weaver (2004) estimated prevalence at 35% among 318 

university students aged 18-25, and Baldwin (2003) estimated 28.2% in 443 STD clinic patients 

aged 18-70. Men’s HPV risk factors include sexual behavior, immune status, and in some, lack 

of circumcision. Some studies identified STD history or inconsistent condom use associated 

with HPV infection as well. HPV Types 16 and 18 are associated with anal, penile, and head and 

neck cancers among men, and HPV-6 and -11 are associated with anogenital warts and RRP 

among men. 

As described earlier, HPV serology is an ELISA-based detection of antibodies to VLPs. The tests 

are type-specific, but since many infected persons do not develop antibodies, ELISA likely 

underestimates the true burden of infection and disease. HPV-16 seropositivity in the U.S., 

estimated from NHANES data, was low at 2.4% for those aged 6-11 years old, and 13% for 

those 12-59 years.

Cervical Cancer in the U.S.

Presenter: Dr. Herschel Lawson, Division of Cancer Prevention and Control 

Overview: Review of cervical cancer and other HPV-related cancers in the U.S.; 

surveillance, disease burden, screening, diagnosis: costs: cervical cancer, cervical cancer 

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precursors, other HPV-related cancers

 

Worldwide, breast cancer is the most common cancer among women. Cervical cancer incidence 

is much lower in industrialized countries than those less developed, where it is the second most 

common cancer in women. The higher burden of disease is very likely due to the absence of 

screening programs in a large part of the developing world. 

Surveillance data on U.S. cervical cancer incidence are collected and housed in the National 

Program for Cancer Registries (NPCR), administered by CDC/DCPC, and the NIH/NCI 

Surveillance Epidemiology and End Results program (SEER). The NCHS, in CDC, houses 

cervical cancer mortality data. 

Cancer incidence in 2002 was 12,000 cases, of which 80% were squamous cancers and 20% 

adenocarcinomas (glandular cancers). There were ~4000 cervical cancer deaths. The American 

Cancer Society estimate for 2005 is 10,000 cases and in 2002, there were 9.2 cervical cancer 

cases per 100,000 women, similar in proportion to cancers of the bladder, pancreas, kidney, 

leukemias and renal disease. That rate was the product of a dramatic decline from the late 1950s, 

when the Pap tests became common. However, there are still racial disparities in the incidence 

and mortality of cervical cancer, with black women still having higher rates than white women. 

The incidence and mortality rates also rise with age, peaking in the late 30s to early 40s, and then 

again in the mid- to late 60s. Death rates increase with age in all groups. 

Interestingly, cervical cancer incidence and death is geographically skewed, highest along the 

Appalachian mountains, in concentrated pockets of the Ohio and the Mississippi River valleys, 

along the Texas-Mexico border, and scattered throughout the country. 

The greatest risk factor (60%) for cervical cancer in the U.S. is not being screened or being 

screened at intervals that are greater than 5 years. Of the 40% of cancers detected in women 

screened, false negative tests, loss to follow-up after positive cytology, and mismanagement 

made up 25-40% of cases and rapidly progressive or hard to detect, uncommon cancers such as 

adenocarcinomas made up 14%-22% of cases. The conventional Pap test has been largely 

replaced in the last ten years by liquid-based cytology. Surveys suggest that 85% of cytology 

testing is currently performed using the liquid-based method. Slides of the two methods were 

shown. The conventional cytology test is known to be less sensitive than liquid-based cytology, 

but more specific than the liquid-based cytology. As a result, more false-positive results have 

occurred requiring additional testing for more women ultimately not found to have cervical 

cancer or pre-cancer.

The NCI reporting system for abnormal Pap results was outlined: atypical squamous cells of 

undetermined significance (ASC-US), atypical squamous cells, cannot rule out high-grade 

disease (ASC-H), low-grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL), and 

squamous cell cancer. For glandular cells, atypical glandular cells (AGC) are reported, as are 

adenocarcinoma in-situ (AIS); and adenocarcinoma. 

Three organizations have issued cervical cancer screening recommendations, ACOG, the 

USPSTF, and the ACS. They agree that screening should begin at about age 21, or within three 

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years of beginning sexual activity. The recommended intervals for screening vary from one to 

three years. 

BRFSS and NHIS data from 2000 were charted to show the prevalence of cervical cancer 

screening cytology done in the U.S. Overall, 82% of women are screened, but more women are 

screened who have insurance than those without it, and fewer foreign-born than native-born 

women are screened. (Swan J et al, Cancer 2003;97:1528-40). There are also racial/ethnic 

disparities, with Asian women least likely (at 71%) to be screened. 

HPV testing. The FDA has approved only one HPV test, the previously-mentioned Hybrid 

Capture II. This is a hybridization assay that amplifies signals with long synthetic RNA probes 

that are sensitive to the 13 high-risk HPV types. It is easy to perform in the clinical laboratory 

and can be automated. The FDA approved this for triage (e.g., to determine if an ASC-US Pap 

test is associated with a high-risk HPV type) and for primary screening to complement the Pap 

test in women aged ≥30 years. In the latter group, if both tests are negative, a three-year 

screening interval should be used. ACOG, ASC, and the ASCCP recommend using the HPV 

DNA test.

The number of Pap tests done annually in the U.S. is not known, but the NCI estimates that a 

base of ~50-60 million Paps per would produce ~2 million ASC-US results; 1 million LSILs (an 

acute HPV infection); ~ 300,000 HSILs, and ~15,000 cancer reports (A. Hildesheim, NCI). Not 

all of the cancer Pap reports turn out tol be invasive cancer. Normal follow up of abnormal 

cytology may include a repeat test, or HPV DNA, vaginal and cervical inspection, colposcopy 

with directed biopsy, endocervical curettage, and manual pelvic examination. 

Cost. CDC modeled HPV’s direct costs at ~$4 billion dollars a year, almost all of which (90%) 

stems from abnormal cervical cytology and treatment of cervical neoplasia. Cervical cancer costs 

accounted for 4% of the total, and management of anogenital warts accounted for the remaining 

6%. Oncogenic HPV is also associated with anal, vulvar, and vaginal cancer, as well as cancer of 

the penis. About 15-20% of oropharyngeal cancer is attributable to HPV types. 

GSK HPV Vaccine Clinical Trial Data

Presenter: Dr. Gary Dubin, GSK 

Overview: New data from the GSK HPV vaccine-development program. 

GSK’s vaccine is designed to prevent cervical cancer in women, particularly from the most 

common types, HPV16- and -18, which cause 70% of cervical cancers. The vaccine uses an 

adjuvant to enhance immune responses to the VLPs. Long-lasting protection is a goal, as the 

vaccine indication will go down to age ten years to prevent invasive cervical cancer and the 

precursors associated with oncogenic HPV infection. 

The GSK vaccine’s VLPs are made from the recombinant L1 proteins of HPV-16 and-18. These 

self-assemble to VLPs that resemble intact virions and prompt immune responses such as the 

generation of neutralizing antibody. The vaccine has 20 μg of each VLP of HPV-16 and-18, plus 

two adjuvant components: aluminum hydroxide and alum plus monophosphoryl lipid A (ASO4). 

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The latter boosts the immune response to VLPs. 

Phase I and II studies assessed vaccine safety, immunogenicity, dose ranging of the VLP 

components, and different adjuvant formulations. In phase IIa studies, the adjuvant vaccine was 

compared to that with only aluminum hydroxide salts and GMT antibody titers were charted for 

HPV-16 and-18. The women received three shots at 0, 1, and 6 months and were followed (to 

now) for up to 48 months. Peak responses of the adjuvant vaccine exceeded the other, and 

approximately two-fold higher GMT functional or neutralizing antibody has persisted. That was 

one reason this formulation was carried forward for testing. 

Two phase IIb studies were outlined. HPV-001 was an efficacy, immunogenicity and safety 

study in the U.S., Canada and Brazil. This followed 1113 subjects over two years for virologic 

and cytologic end points, and biopsy-confirmed CIN lesions. HPV-007 extended -001 for 

another two years. 

New data. To date, the AS04 adjuvant has been assessed in vaccines under development other 

than HPV in 40 completed and 3 ongoing studies involving >16,000 subjects and 43,000 vaccine 

doses. The AS04 vaccines have been generally safe and well tolerated. The two largest programs 

are, 1) of a genital herpes simplex virus (gD ASO4) vaccine now in large Phase III trials, 

including a collaborative NIH efficacy trial; and 2) the development program for Fendrix®, 

which is targeted to hemodialysis patients who respond poorly to the standard hepatitis B 

vaccine. It was approved by the E.U. in early 2005. 

HPV-001 efficacy study. This double-blind, randomized controlled trial involved 1113 women 

assigned to either the HPV vaccine or alum control, followed for 18-27 months from enrollment. 

The endpoints were HPV-16 and-18 infections and associated cytologic abnormalities and 

cervical lesions. The vaccine was shown to be safe and well tolerated, inducing antibody 

responses at titers higher than natural infection in almost all subjects. Efficacy was high, with 

100% protection against persistent (6 months) HPV-16 or -18 infection, and the same for biopsyconfirmed CIN lesions with demonstrated HPV-16 or-18 in the DNA; protection from abnormal 

HPV-16/18 Pap smears was 93%. There was also preliminary evidence found of protection 

against other oncogenic HPV types (31 and 45), which are phylogenetically related to HPV-16 or 

-18. 

HPV-007 was a long-term, blinded follow-up to -001, which evaluated the same end points as 

the initial trial over another 36 months. Preliminary interim analysis has been done of the first 

12 months of follow-up, providing a total of 48 months with the parent studies. The extension 

involved 776 subjects randomized to the intent-to-treat cohort. Efficacy was assessed against 

incident infection for HPV-16 or-18; persistent infection (6- and 12-months), abnormal 

cytologies associated with HPV-16 and-18, and biopsy-confirmed CIN lesions. The demographic 

characteristics of the enrolled subjects were outlined. 

Immunogenicity. Study -001 revealed a peak antibody response to HPV-16 and -18 at month 

seven. By about month 18, antibody titer declines to a plateau at about one log lower than the 

peak, but still tenfold higher than that from natural infection with either HPV-16 or -18. Over 

98% of subjects maintained seropositivity for HPV-16 or -18, even to month 53. 

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Efficacy. VE was 100% over two years of follow-up against persistent infection and CIN lesions. 

VE was also 100% during the extension phase to year four against 12 month persistent infection 

and CIN lesions, showing good duration of protection. In addition, the vaccine was most 

efficacious against the end points with the highest predictive values for cervical cancer (i.e., 12 

month persistent infection or a CIN lesion). No subjects in the vaccine group developed either 

CIN 1 or CIN 2 or worse lesions associated with HPV-16 or -18, although some of the controls 

did. Efficacy also was ~96% for ASC-US or worse cytologies associated with HPV-16 or-18. 

Vaccine efficacy was also maintained for the four years of follow-up against virologic end points 

(incident infection and 6- and 12-month persistent infection, with efficacy levels of 94.7%, 96% 

and 100%, respectively). Study -007 looked for evidence of waning protection, which might be 

signaled by increasing numbers of endpoints in vaccine recipients. Instead, during the HPV-007 

study, VE against incident infection with HPV-16 or -18 remained high, at 95.8% and 100%, 

respectively ─ in fact, higher than those seen in the first two years of follow-up. 

Conclusions. Almost 100% seropositivity was maintained out to 53 months after study 

enrollment. Protection did not wane through a mean of 48 months for virologic, cytologic or 

histopathologic end points (including incident and persistent infections). There were no vaccinerelated serious adverse events in any portion of the studies. 

Phase III studies are underway. One is GSK’s multicenter, double-blind, randomized controlled 

trial (HPV-008) in 14 countries using hepatitis A vaccine as the control, and involving >18,000 

women aged 15-25 years. NCI is doing a second Phase III study (HPV-009) similar to GSK’s, 

but in a population-based efficacy study in Costa Rica with six study centers and 7500 women 

aged 18-25 years. Both studies are assessing VE against CIN 2-plus lesions associated with 

HPV-16 and -18 as the primary end point, and both have independent DSMBs. 

Additional “age-bridging” trials are being done to extend down to age 10 and past age 25. This is 

hoped to provide protection before sexual debut, as well as protect women aged >25 who remain 

at risk of new HPV infections. 

 HPV-012, which targets preteen and adolescent girls, is an immunological bridging study 

to compare the immune responses of girls aged 10-14 to those aged 15-25 years, as well 

as safety and reactogenicity. Results: The safety profile was similar between the 10-14 

year-olds and the 15-25 year olds, but the 10-14 year-olds’ GMTs were more than twofold higher than those of the 15-25 year-olds. There were no serious adverse events 

related to vaccination and the reactogenicity profile was the same for all the groups.

 Recently completed, HPV-013 studied safety and immunogenicity in 10-14-year-old 

girls. Those data should be presented in the near future. 

 HPV-014 is an immunological bridging study of women aged 25 years, comparing their 

immune responses to those of the 15-25 year-old efficacy cohort. 

A timeline of the Phase III studies was shown from 2005 to 2009, involving >30,000 subjects. 

The efficacy studies HPV-008 and HPV-009 will go at least through 2009, as will the long-term 

follow up of the adolescent safety study to examine the kinetics of antibody responses, especially 

in the 10- to 14-year age range over time. Another long-term follow-up to 2007 will be done to 

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compare immune responses of women aged >25 to those aged 15-25 years.

Data will be released over the next few months for HPV-013 (adolescent safety data), HPV-014 

(immunobridging 15-25 years and 26-55 years), more data from HPV-007 (overall efficacy 

against cytological/histological endpoints regardless of HPV DNA lesion status), and health 

economic modeling data. 

 

GSK plans to apply for U.S. licensure by year’s end, and also will file for European licensure 

this year. Post-licensure work will study efficacy in >5000 women aged >25 years, assessing 

persistent infection and CIN over at least three years; the vaccine’s co-administration with 

routine adolescent vaccines; and safety and immunogenicity in HIV-positive women. Phase IV 

studies being planned include long-term follow-up (10-15 years) of cancer and pre-cancer among 

>5,000 Phase III subjects in Finland. Other Phase IV studies should begin in 2007. 

GARDASIL® Presentation 

Presenter: Dr. Eliav Barr, Merck & Co., Inc.

Overview: GARDASIL® description; GARDASIL® clinical trials design, focusing 

on the choice of efficacy endpoints and target populations; clinical trials results. 

The primary analysis of Merck’s Phase III trials in adolescents and young women have been 

completed. The vaccine targets HPV types 16, -18, -6 and -11. HPV-6 and -11 are responsible 

for >90% of genital warts and recurrent respiratory papillomatosis (RRP) lesions in both 

boys/men and girls/women. These types also cause 10% to 15% of CIN 1 lesions. Because 

HPV-6 and -11 related CIN 1 lesions are morphologically indistinguishable from the HPV-16 

and-18 CIN 1 lesions, they therefore are treated as precancerous, imposing an additional 

economic and psychologic burden. 

Studies of GARDASIL® have been conducted in women and in men. While the clinical sequelae 

of HPV infection are better understood in women vs. men, HPV infection imposes a heavy 

burden on men (cancer, RRP, genital warts). Men also represent the primary mode of HPV 

transmission to women. 

GARDASIL® is a quadrivalent, virus like particle (VLP) vaccine. It is not a live virus. It has 

four VLP types manufactured in yeast with Merck’s proprietary aluminum adjuvant. It is given 

in three doses at day 1, month 2 and month 6. The vaccine must be stored at 2oC to 3oC. FDA 

has granted priority review for Merck’s December 2005 application for licensure and the action 

date is June 2006. Prophylactic administration of the vaccine has been shown to prevent HPV-16 

and -18 related cervical, vulvar, and vaginal cancer, as well as HPV-16 and-18-related CIN 2, 

CIN 3, and AIS, and VIN 2/3 and VaIN 2/3, the precursor lesions to vulvar and vaginal cancer. 

Prophylactic efficacy was demonstrated for all four HPV types for infection, low-grade 

dysplastic lesions, genital warts, and low-grade flat warts, for 9-15-year-old boys and girls and 

16-26-year-old adolescent and young adult women. Future applications will provide data to 

extend the age indication to young adult men and women aged >26 years. 

Study design. The trials’ primary end points were prophylactic efficacy for HPV-related cervical, 

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vulvar, and vaginal cancers and their precursors, genital warts, and persistent infection. 

Additional end points were the vaccine’s impact on HPV disease burden in women and on the 

course of existing HPV vaccine-type infection. 

End points. Clinical trials for a vaccine to prevent cervical cancer are not possible because HPV 

infection takes ~20 years to become cancer, and due to the requirement to provide cervical 

cancer screening women during the trial thereby treating subjects before they develop the 

cancer). So, intermediate end points were selected: initial HPV infection (which normally 

clears), HPV-related CIN 1 (important from a health-economics perspective), and most 

important, CIN 2/3 and adenocarcinoma in situ, the intermediate and obligate precursors to 

cervical cancer and the targets of screening programs. Preventing CIN2/3 and AIS prevents 

cervical cancer. Demonstration of prophylactic with respect to CIN2/3 and AIS cause by 

vaccine HPV types was approved by the FDA advisory committee as the basis for U.S. licensure. 

HPV-related vulvar and vaginal cancers have the same natural history. Vulvar cancer incidence 

is rising among young American women. HPV, primarily HPV-16 and-18, being involved in 

~70% of vulvar and vaginal cancer biopsies. Their immediate precursors are the VIN 2/3 and 

VaIN 2/3 lesions, which have a high rate of progression to cancer. 

Immunogenicity. It will be particularly important to protect 9-15 year-old children using 

prophylactic HPV vaccines, as such subjects are sexually-naive and HPV infection occurs 

shortly after sexual debut. The efficacy of GARDASIL(R) in 16- to 26-year-olds was bridged to 

pre-adolescents using an immunogenicity bridging program. Long-term efficacy data are being 

generated to find immune correlates and to define the duration of immune response to 

GARDASIL®, in order to address HPV’s lifelong risk for women. Also pursued were data on 

co-administration with other common adolescent vaccines. Vaccine safety was evaluated in all 

the populations indicated, and a pregnancy outcomes follow-up program in clinical trials of 

GARDASIL vaccines was established. Understanding the vaccine-pregnancy interaction is 

important, since the vaccine will be administered for women of childbearing age. 

HPV infection risk is closely tied to sexual debut. The proportion of 10- to 14-year-old subjects 

with evidence of HPV disease is low. However, after sexual debut, the proportion of the female 

population with evidence of HPV disease rises dramatically. The peak incidence of new HPV 

disease in women occurs between ages 16 and 25 in both men and women. The clinical efficacy 

trials focused on 16-26 year-olds, the period of highest risk to acquire HPV, as well as the period 

of most cytologic abnormalities and rates of CIN. This group would benefit dramatically from a 

prophylactic HPV vaccine. Immunogenicity bridging studies were done to demonstrate an 

immune response in the younger age group. Studies are being done to evaluate the VE for 

women aged ≥24 years. Those efficacy data should be available in 2007. 

Clinical trials were outlined, involving 27,000 women and children on four continents. The goal 

was to include broad SES and ethnic background, sexual behavior, and concomitant disease 

information to allow generalization to the overall population. Different Pap test abnormality 

management also was considered, as seen in the U.S. and around the world. Centralized 

cytology, biopsy processing, and HPV typing will ensure accuracy in the end-point 

ascertainment (diagnoses of HPV-related clinical disease). VE will be analyzed for preventive 

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and prophylactic efficacy, and post-exposure prophylaxis therapeutic efficacy will be 

investigated). The validation programs were presented for approval to regulatory authorities. 

• Protocol 005 (P005) involved 2391 women aged 16- 23 years old, 400 of whom will be 

followed through seven years. 

• P007 involves 1155 women aged 16-23 years old. An immune memory

evaluation will begin in year 5. (booster dose given at Year 5) is nearly complete.

• Future I trial of VE for CIN1/warts involves 5442 women aged 16-23 years.. The CIN 

(any grade) endpoint was chosen to evaluate the vaccine against the full spectrum of 

clinical HPV disease. CIN 1 usually resolves on its own, but incurs high healthcare costs. 

VE for HPV-6, -11, -16, and -18 related CIN was 100%, highly statistically significant. 

Because HPV-6 and -11 significantly contribute to CIN 1 incidence, that VE is important 

to maximally reduce morbidity, the costs of cervical cancer screening and HPV disease in 

women. VE was 100% for external genital lesions mostly due to HPV-6 and -11. The 

study is ongoing to allow for evaluation of the efficacy of the vaccine over a longer period 

of time. The study is expected to end by the end of 2006. 

• Future II trial of VE for CIN 2/3 and AIS involved 12,167 women aged 15-26 years. This 

also could be extended, and it will be followed by a duration of efficacy registry study

in the Nordic region. A study of Norwegian HPV surveillance and VE on disease 

burden/population effectiveness will also be done. Future II Results: VE for both HPV16 and-18 components was demonstrated a statistically significant difference: no cases in 

the vaccine group, and 21 cases in the placebo group. The study is ongoing to allow for 

evaluation of the efficacy of the vaccine over a longer period of time. The study is 

expected to end by the end of 2006. In addition, subjects in the Nordic region will be 

followed for long-term duration of efficacy. A study of Norwegian HPV surveillance and 

VE on disease burden/population effectiveness will also be done. 

• Studies of prespecified prophylactic efficacy analyses in the integrated database of 

efficacy studies were also conducted. These studies involved a total of 20,541 subjects 

who were randomized and received at least one dose of vaccine/placebo. This integrated 

analysis showed: 

o

o

o

100% prophylactic efficacy with respect to HPV 16- and HPV 18-related CIN 2/3 

and AIS, a highly statistically significant result. 

100% prophylactic efficacy with respect to HPV 16- and HPV 18-related CIN 3 

and AIS (include high grade cervical dysplasia, squamous carcinoma in situ, 

and adenocarcinoma in situ). 

100% prophylactic efficacy with respect to HPV 16- an dHPV 18-related VIN 2/3 

and VaIN 2/3, the precursors to vulvar and vaginal cancer. 

• A Phase III Immunogenicity trial will involve 4800 boys and girls aged 9-15 years has 

been completed. It will be followed by a 36-month extension to study VE in adolescents 

to evaluate the duration of vaccine immunogenicity in this population. 

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• An efficacy study of women aged to 45 years will be done, concurrently with a study of 

VE in 16- to 26-year-old men

The baseline characteristics of the trials’ participants were outlined: mean age of 20, most 

sexually active, diverse history of past pregnancy, common use of hormonal contraception; 

relatively high rate of chlamydia. Overall, ~12% (14% in the U.S.) had a diagnosis of ASC-US 

or worse, suggestive of cervical intraepithelial neoplasia. Some (27%) of the women were HPVpositive to at least one vaccine, but most were so to only one HPV type. 

There were two analysis populations: 1) per protocol, the primary specified analysis, consisting 

of women naive to the relevant HPV type at enrollment, who remained so throughout the threevaccination regimen; and who received the full 3 dose regimen. Case counting started 1 month 

after completion of the 3-dose vaccination regimen; and 2) modified intention to treat, consisting 

of women naive to the relevant HPV type at enrollment. Case counting started 1 month postdose. The MITT population was the broadest possible baseline naive population. They included 

people who became infected before they received the full vaccination regimen, subjects who 

received only one or two doses of vaccine, or in an non-ideal manner, or who had violated the 

protocols in many different ways. VE was still 94% and 95% respectively, for CIN and for 

external lesions. 

VE in women infected with vaccine HPV types. Study data demonstrated that women positive for 

one HPV type benefited from continuing VE for the other three HPV types, at ~90% for CIN and 

the same for external genital lesions. A new analysis also demonstrated VE to modify the natural 

history of HPV disease. Serology and cervical-vaginal cytology was done at Day 1 to test for 

active HPV infection. VE was explored for two groups: 1) women who were seropositive and 

PCR negative, that is, those who were infected before enrollment and whose immune response 

cleared that infection. The study explored whether the vaccine could induce an immune 

response to help prevent progression to CIN 2/3. Also explored was 2) whether the vaccine could 

help women who were infected with a vaccine HPV type but had not mounted an immune 

response to that infection and 3) whether the vaccine could help women positive to both tests, 

who had chronic infection and a high level of CIN 2/3. VE was in doubt here, because these 

women had already mounted an immune response and failed to clear infection. 

Results. The vaccine was efficacious in women with evidence of previous HPV infection but 

who cleared that infection. The low event rates were consistent with the protective effect of 

natural immunity to HPV. But the event rates were not zero, and 100% VE suggested an 

ability to prevent recurrence of the disease caused by the relevant HPV type. For women with 

early infection or who failed to mount an immune response to the infection, GARDASIL® 

reduced progression to CIN 2/3 by 28% but the lower bound of the 95% confidence interval for 

efficacy included 0%, so this is only a trend that needs to be evaluated further . And as expected, 

the vaccine could not do much to help women with chronic HPV infection to create further antiHPV. 

An analysis of VE for CIN 2/3, regardless of the causal HPV type was done for two groups: 1) 

those who were naive to all vaccine HPV types (no testing was done for non-vaccine HPV 

types), to approximate adolescents just before sexual debut, and to evaluate VE to prevent the 

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development of cervical cancer overall, and 2) an “all-comer” population of women who are 

sexually active and present for care. Cases were counted immediately after vaccination for 

incident disease caused both by vaccine and nonvaccine HPV types. 

Preliminary data indicate a steadily rising benefit for the vaccinated naïve group compared to the 

placebo group, that becomes increasingly apparent with each screening round and resulting in a 

dramatic reduction in the overall rates of CIN 2/3 caused by any vaccine HPV type. For the 

second, “all-comer” population, which included women infected or with CIN 2/3 at baseline, the 

same pattern emerged. While prevalent disease is clear, the VE even for CIN 2/3 becomes visible 

very shortly after the follow-up begins, and is increasingly apparent over time. The same pattern 

repeated for genital warts. 

The cost implications of these outcomes to health economics are evident. Even the short-term 

follow-up of the Phase III studies have already shown a significant decline in the number of 

women with abnormal Paps that require a visit for colposcopy. A reduction by 20% of the 3 

million annual ASC-US cases in the U.S. equates to 600,000 less tests; a 33% reduction of the 

300,000 HSILs per year equates to 100,000 less cases. The clinical trials referred women to 

biopsy for almost any lesion, and a reduction was still evident. That is expected to increase over 

time, as are genital biopsies and genital definitive therapy. 

 

The Phase III program will end early. When the overwhelming VE was demonstrated with a 

favorable safety profile, the DSMB mandated that women in the placebo groups receive 

accelerated vaccination. 

The finding of 100% efficacy precluded the ability to find an immune correlate of efficacy. With 

no breakthrough cases due to waning immunity, the minimum protective anti-HPV level could 

not be determined. However, the results after 48 months of follow-up showed persistent antiHPV levels. These declined to a plateau level paralleling the anti-HPV levels in women who are 

seropositive and PCR negative at baseline from a natural immune response that cleared HPV 

infection. Additionally, the 100% VE determined against persistent infection and HPV-16 related 

CIN 2/3, with no breakthrough infections, reflects well upon long-term protective efficacy. The 

Scandinavian population-based, long-term follow-up will assess that. The women enrolled were 

vaccinated in 2002; U.S. vaccination is expected to begin in June of 2006. The Scandinavian 

cohort will be a good sentinel cohort, and will be analyzed over time for breakthrough infections. 

That will inform any possible need for booster doses. 

Finally, Merck explored whether anti-HPV levels are needed to protect against infection and 

disease or if, like hepatitis B, a vaccine might just induce a strong anamnestic response that 

aborts disease even in the absence of detectable serum anti-HPV. Merck followed the 24% of 

women in the trials who vaccinated, mounted high anti-HPV 18 levels, but then nominally seroreverted by Month 24. High levels of protection remained for HPV-18 related disease when 

followed over six-month intervals, even in the 24% of the population who had no detectable antiHPV-18. That suggests long-term vaccine protective efficacy and a potential anamnestic 

response, and the latter is the sign of long-term vaccine efficacy. 

Also interesting is that pre-adolescents seemed to mount an immune response even more intense 

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than that of the adults. Recent data of sentinel adolescent cohorts also show adolescents’ immune 

response remaining much higher than that seen in adults, even a year after the vaccination 

regimen. That is important because month 18, one year after dose 3, is the where the plateau 

begins. 

 

An analysis was done to evaluate whether administration of one dose of vaccine in women who 

are seropositive at baseline will induce an anamnestic response. These women had much higher 

anti-HPV levels two months after dose 1 than women who were baseline naïve, and given the 

two-month lapse, that could even be an underestimation of the initial high anti-HPV level in such 

women. A mechanistic study is now underway to see if a long-term administration of a dose at 

five years after enrollment provides the same kind of anamnestic response. Preliminary data are 

encouraging that these vaccines can induce memory immune responses that are highly active and 

result in a robust reconstitution of anti-HPV levels, indicating likely long-term protection. 

Safety data were shared from a cohort of 27,000 enrolled women, divided into groups receiving 

monovalent vaccines or other quadrivalent vaccine formulations, and those receiving 

GARDASIL.® Serious adverse event rates were very low, at 0.5% for the other vaccines versus 

GARDASIL’s ® 0.4%. Women in both groups recorded events on their vaccine report cards. 

Serious vaccine related adverse events were rare and the discontinuation rate was extremely low. 

Systemic events were comparable. Injection site adverse reactions were slightly higher in the 

GARDASIL® group, but half of those were from the injection itself, and were comparable to the 

reactogenicity seen with other adolescent vaccines. Rates of fever were slightly higher in the 

GARDASIL group, but most were very low grade; very high-grade temperature rates were the 

same to placebo. 

Children aged 18-26 years, 9-17 year-old girls and 9-15 year-old boys received GARDASIL, and 

were compared to adult women. Injection site AEs were lower in the children, as were systemic 

AEs, while serious AEs were comparable. The safety profile appeared to be unaffected by the 

baseline HPV status of the recipient.

Pregnancy outcomes evaluated included medical history during the pregnancy, mother and 

child’s outcomes in the neonatal period, causes of spontaneous abortion, and elective termination 

were all examined. Infants were followed to the end of the study to look for late events not 

detected in the neonatal period. Natural history studies of pregnancy in which pregnancy 

screening with beta-HCG is used indicate rates of spontaneous abortion at 15%-20%, but the 

clinical trial’s use of beta-HCG screening found rates of 28%-33%. Congenital abnormalities 

occur in ~3%-4% of live births in the general U.S. population. 

Approximately10% of subjects became pregnant during the trial, even though subjects were 

instructed to use contraception during the vaccination phase of the study. Of the known 

outcomes (those “unknown” had just not given birth when the database was closed) live births 

were predominant, with rates comparable between the two vaccination groups. In terms of 

pregnancies that began close to vaccination versus pregnancies ≥30 days of vaccination, the 

normal-baby outcomes were comparable, as were spontaneous losses. Rates of both elective and 

spontaneous abortions within 30 days of a vaccination were slightly lower in the group that 

received GARDASIL® compared to the placebo group. 

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The rates of congenital abnormalities were comparable to those in the general population and 

similar between the GARDASIL® group (15) and the placebo group (16). But the distribution 

was slightly different; five cases occurred within 30 days of the vaccination of the GARDASIL® 

group, and none in the placebo group; and the opposite occurred for those becoming pregnant 

≥30 days after vaccination, with ten in the GARDASIL® group and 16 in the placebo group. 

The five cases involved common congenital anomalies associated with late fetal injury far after 

vaccination. Merck’s developmental and reproductive toxicology preclinical modeling also 

showed no association of congenital anomalies to GARDASIL® vaccination, even during 

pregnancy and even at the most vulnerable period. The DSMB, study steering committee, and an 

expert teratologist were in consensus that GARDASIL® does not impact pregnancy outcomes in 

any way.

 

Post-licensure evaluation includes a large pharmacovigilance program involving 35,000 women. 

It will monitor general safety and pregnancy outcomes, establish pregnancy registry, and 

evaluate long-term efficacy. Through the central Nordic registry, long- and short-term efficacy 

and safety will be evaluated on a population basis in real time. 

 

Discussion of the presentations to this point included: 

• The SAE rate for those PCR negative was 0.6, but twice that for those PCR positive. The 

SAE rates, particularly in the seropositive population, were multiple events that were not 

vaccine related (e.g., motor vehicle accident, sports injuries), presenting no signal. 

• Since teenage girls develop genital warts earlier than males, are they not the 

transmission route to young men? The answer lies in data on the age of the young 

women’s first partner for their sexual debut. The partner is typically substantially older 

and more experienced than the girl. A survey in Iceland indicated on average a three-year 

older partner. Transmission is probably back and forth, but for herd immunity, 

vaccination of men will be important for HPV. 

• The bridging to age groups was done based on serum antibody from vaccine 

administered intramuscularly, but natural infection produces little serum immunity. 

Given that, is that a good correlate of efficacy? Dr. Barr defined the bridging as a 

standard approach for many vaccines to examine populations in which efficacy cannot be 

measured, compared to populations in which efficacy is demonstrated. The only other 

way to definitively show this will be through very long-term, efficacy data. But the fact 

that the vaccine-induced anti-HPV responses were higher in children than adults, where 

the VE was definitive, satisfies the prerequisites to bridge that VE to the younger 

population. Dr. Dubin agreed, and added that the role of serum antibody in protection is 

proven by preclinical animal studies showing passive antibody transfer to other animals 

who then resisted challenge. Additionally, most of antibody in cervical secretions is 

transudated from serum antibody. Measurement of cervical antibody levels is not 

feasible, both from a collection standpoint and due to no standardized methodology for 

measuring cervical secretion antibodies. Those considerations support the use of serum 

antibodies as a reasonable measure of the immune system element that mediates 

protection, particularly since the vaccine study data indicate that the cervical antibody 

levels will correlate reasonably well with the serum levels. 

• Dr. Dubin commented that data on HPV incidence or prevalence indicate that oncogenic 

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HPV infections have some relationship to age at infection. The highest rates are among 

younger women and they drop with age. Whether this pertains to less exposure in women 

aged >25, or to partial protection that's acquired from previous exposures, is unclear. 

Either way, although the absolute rates are lower in older women than those younger, 

new incident infections occur; and the overall absolute risk continues even with older 

age. Dr. Barr agreed. Merck’s Phase III database showed the highest infection incidence 

in 18-year-olds, that that slowly declines with age. But no data can indicate whether age 

of receipt changes VE; all that is known from current data is that the VE is comparable 

regardless of the age of the recipient. 

• Dr. Barr reported that antibody levels were somewhat higher among people who were 

PCR positive but serologically negative, but not as dramatically high as among the 

baseline seropositives. 

• Dr. Plotkin asked Dr. Lowy for his opinion of whether an L1/L2 vaccine might provide 

additional breadth of immunity. He answered that in vitro studies show that the L2-only 

vaccine can induce cross-neutralizing activity, but at substantially lower titers than with 

the L1-VLP vaccine. The immunodominance of the L1 vaccine causes animals, exposed 

to L1/L2 VLPs, to be essentially naïve to the L2. L2 has not been used in human clinical 

studies. 

• Dr. Martin Meyers asked Dr. Dunne if there was any chance that the 2.4 prevalence rate 

in children aged 6-11years might come from maternal infection, or early sexual 

encounter. She could not say, since these data were from NHANES, which does not 

collect data on sexual risk or other exposure. 

• Since the antibody concentrations after the three-dose schedule are so much higher than 

those from natural infection, Dr. Georges Peter if consideration was given to a two-dose 

primary schedule, or one dose that is boosted five years later. Dr. Dubin responded that 

the significant rise in antibody titers at the third dose, greater than that after the second 

dose, also suggests that two doses do not convey the maximum immune response. That 

level may still be protective, something that could be shown if a correlate of protection is 

ever developed. For now, the overriding consideration has been the greater duration of 

protection afforded by such a significant boost, something important in a vaccine to be 

given down to age ten years or even younger. 

• Dr. Abramson asked what Merck would seek in its FDA licensure application as regards 

issues of pregnancy, since many recipients could potentially be pregnant. Dr. Barr said 

that Merck states that pregnancy should be avoided during the course of vaccination, and 

then provides all the information on the vaccine. There are no data on the use of this 

vaccine in pregnant women. For that reason, they would recommend that FDA label the 

vaccine as Pregnancy Category B, to avoid the use during pregnancy, and allow 

flexibility in the dosing regimen to accommodate pregnant women. 

Cost Effectiveness of HPV Vaccination

Presenter: Dr. Harrell Chesson, Division of STD Prevention 

Overview: Ongoing and published cost-effectiveness studies of HPV vaccination in 

the United States.

Models are important in evaluating the cost-effectiveness of HPV vaccination, because many 

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factors affect the costs and benefits of HPV vaccination, such as: vaccine efficacy, coverage and 

duration, HPV infection natural history, rates of HPV transmission, and cervical cancer 

screening factors such as coverage and frequency. Many of these factors are unknown or not 

known with precision at this time. Models are the only way to take these factors into account 

and project the possible impact of HPV vaccine.

The literature on HPV vaccine cost-effectiveness (CE) has used Markov models (also called 

cohort models or health-state transition models) of the natural history of HPV infection. HPV 

transmission, and occasionally the natural history of HPV infection, are addressed with dynamic 

models. 

The advantages and disadvantages of each were outlined. Since the Markov models do not 

include HPV transmission effects (or herd immunity), they are not as useful when the effect of 

transmission is important (e.g., cost/benefit of adding males to a female-only vaccination 

program). Leaving out the transmission effects could understate the vaccination’s benefits. 

However, the Markov models may be able to establish a reasonable upper bound of the cost per 

quality-adjusted life-year (QALY) gained by vaccination. 

Dynamic models do include HPV transmission effects, or herd immunity, so they can better 

evaluate vaccination scenarios in which transmission effects are important. But, while the 

inclusion of transmission may make them more realistic, it also introduces additional uncertainty 

from parameters such as sexual-mixing behaviors and transmission probabilities. 

A Markov model of the natural history of HPV infection was shown. It plotted a person’s 

movements from one state of health to another at defined and equal intervals, or Markov cycles. 

The probability of transition can be made dependent on characteristics such as age. The dynamic 

compartmental model of HPV transmission places the population into a few compartments (e.g., 

vaccinated, susceptible, infected) that can then be further stratified based on characteristics such 

as age, sex, and sexual activity level. The rate at which persons move from compartment to 

compartment can be a function of many factors (e.g., moving from susceptible to infected 

depends in part on HPV prevalence). Differential equations are used to model the spread of 

infection over time. 

Markov models. Three studies using the Markov model to evaluate the CE of HPV vaccination 

in the U.S. were outlined: 

• Sanders and Taira (Emerging Infectious Diseases,2003;290:37-48) examined the 

benefits of adding an HPV vaccine to current U.S. cervical cancer screening. They 

assumed that 71% of women were screened every two years. Their model examined a 

vaccine targeted against high-risk HPV types in general. In the base case analysis, age of 

first vaccination was 12 years; vaccine coverage was 70% and VE was 75%. Female-only 

vaccination was estimated to reduce cervical cancer incidence in the vaccinated cohort by 

20% at a cost per QALY of $22,800; with a lifetime duration of protection, the cost per 

QALY was $12,700. 

• Goldie et al (Journal of the National Cancer Institute, 2004;96:604-615) examined 

the benefits of adding a vaccine for HPV-16 and -18 to the current U.S. cervical cancer 

screening. The assumptions about current screening practices were based on reports that 

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67% of women were screened within one year, 28% had been ≥1 year since their last 

screening, and 5% had never been screened. In the base case analysis, age of first 

vaccination was 12 years; vaccine coverage was 100%, and VE was 90% Vaccine 

duration was lifelong and the vaccination costs was $377 per series Results: Cost per 

QALY gained for female-only vaccination was $24,300. As VE rises from 70%-100%, 

the 46% reduction in the lifetime risk of cervical cancer increases to 66% and the cost per 

QALY drops from ~$33,000 to ~$20,000. 

• Kulasingam and Myers’ model also examined a vaccine targeted against high-risk 

HPV types in general. In the base case analysis, age of first vaccination was 12 years; 

vaccine coverage was 100% and VE was 90%, with a 10 year duration of protection. 

This study focused on the cost per life-year gained rather than the cost per QALY gained. 

They found the most CE strategy costing <$50,000 per life year gained to be vaccination 

plus biennial screening, delayed until age 24 years. That resulted in ~$45,000 per lifeyear gained, compared to a strategy of no vaccination and screening every three years 

beginning at age 18. 

In the sensitivity analyses across the Markov model studies, the cost per QALY gained for 

female-only vaccination ranged from <$10,000 to >$100,000. The CE estimates were most 

sensitive to cervical cancer screening issues such as frequency and age of initiation, but the 

duration of VE also impacted the CE. The CE effectiveness estimates were least sensitive to 

reasonable changes in the natural history parameters and the screening test characteristics. 

Dynamic models. The dynamic model used by Taira et al. (Emerging Infectious Diseases 

2004:10(11):1915-23) examined vaccine targeted to HPV-16 and -18 with 90% efficacy. The 

Merck modelers, Elbasha and Dasbach (in progress) examined a quadrivalent vaccine with 90% 

efficacy against low-risk types and 70% efficacy against high-risk types. 

Both models assumed vaccination at or before age 12 years with 70% vaccine coverage. The 

vaccine duration ranged from ten years to lifetime; vaccination cost per series was $300-$500. 

Merck’s model set a per-partnership HPV-transmission probability of 0.8 for male to female 

transmission and 0.7 for female to male. The frequency of annual cervical cancer screening 

ranged from 0.6%-60.4%, varying by age. The study population was divided into 15 age groups 

and three sexual activity groups, the latter based on rate of new sex partners per year. There was 

assortative mixing, meaning that sex partners are more likely to be of similar age and sexual 

activity level than would be expected if partners were selected randomly. The QALY cost for 

two strategies was charted: no vaccination and cervical cancer screening only, and addition of 

female vaccination to the screening program. The cost per QALY gained of adding female 

vaccination to an existing cervical cancer screening program was $728. The Merck model 

posited an 8% reduction in steady-state cervical cancer incidence for those aged ≥12 years, with 

a ten-year duration of immunity, and incidence reduction rose to ~35% with a lifetime duration 

of immunity. 

The Taira model was a hybrid dynamic-Markov model. While the dynamic model generated 

HPV incidence estimates, the Markov model was used to convert the incidence estimates to 

QALYs and costs. The assumed per-partnership transmission probability was 0.35 for the 

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youngest age groups, which decreased gradually to 0.15 for the oldest group. The population was 

divided into nine age groups and four sexual activity groups, with assortative mixing by age and 

sexual activity level. The cost in QALYs again was charted for no vaccination and screening 

only, and female vaccination added to screening. Again, the latter increased the total cost (by 

$244 per woman) but it also increased QALYs by .0167 per woman (or 6.1quality-adjusted lifedays), yielding a CE ratio of about $14,500 per QALY. This model showed a 62% reduction in 

the lifetime risk of cervical cancer and a 95% reduction of lifetime cervical cancer cases related 

to HPV-16 or -18 in the vaccinated cohort. 

The cost per QALY as estimated using the Markov models ($22,000-$24,000) exceeded that of 

the dynamic models ($700-$14,600) in part because the Markov models excluded the benefits of 

herd immunity. Additionally, the Merck model’s lower cost per QALY is attributable in part to 

the inclusion of the benefits of preventing HPV-6 and -11. However, these are base-case 

estimates, and the estimated CE ratios can vary substantially when base-case assumptions are 

varied. The limitations of the models must be considered, including the uncertainty of HPV 

transmission dynamics, the duration of naturally acquired immunity, and the non-inclusion of all 

possible vaccination effects (e.g., possible decreased positive predictive value of the Pap with 

rising vaccination coverage). The models do not consider that AEs may incur cost or reduce 

QALYs; that vaccination may affect sexual behaviors or health-seeking behaviors; or the 

prevention of other HPV-related cancers besides cervical cancer. Including the benefits of 

reducing other HPV-related cancers would improve the estimated CE of vaccination, as would 

the inclusion of averted indirect costs such as productivity loss due to cervical cancer. It is 

possible that small changes in a large number of parameter values could affect the results; as 

such more comprehensive sensitivity analyses may be warranted. Finally, future studies will 

further examine the CE of male vaccination and other factors affecting vaccination CE, such as 

age at vaccination and catch-up vaccination. 

Mathematical Modeling of HPV Vaccine

Presenter: Dr. Geoff Garnett, Imperial College, London 

Overview: Impact of HPV vaccines, considering transmission dynamics and disease 

progress, modeled in two ways; one focusing on the interaction between HPV types and 

cervical cancers and the other focusing on age of vaccination and catch-up programs. 

Modeling was presented of a quadrivalent HPV vaccine delivered in the setting of routine 

cervical cancer screening. The model included the natural history of HPV infection and disease, 

estimated parameters and calibration, vaccine impact on cervical cancer, precancerous 

abnormalties and genital warts, the impact of vaccinating women alone versus both genders, 

duration of vaccine-derived protection, and age of vaccination and catch-up programs. Inclusion 

of coinfections could make the model complex beyond utility. 

A modeling framework was shared to describe HPV-16’s and -18’s natural history process, 

delineated to precancers, neoplasias, and three types of lesions. The model’s focus was on CIN2 

LSIL and HSIL, considering both screening and natural regression of infection (transient 

infection), and effective treatment of chronic infection, through to stage four cervical cancer and 

death. For HPV-6 and -11, which lead to lesions and warts rather than cancer, the model 

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assumed a population of infected susceptibles who are vaccine protected, or not. The latter would 

be either asymptomatic or symptomatic with warts, which could either regress back to an 

asymptomatic stage, recur, or reach immunity. Another variable considered was loss of vaccine 

protection leading to renewed susceptibility. Type-specific natural immunity of five years, and 

then lifelong, was assumed. 

The model was calibrated based on data on sexual behavior and age of sexual debut reported by 

the National Survey of Family Growth, which was compared to observed prevalence of HPV 

infection (Marhart et al, 2005) as well as to SEER mortality data. Future analysis will include 

age-specific patterns of infection and disease.

High transmission probabilities per sexual partnership were required to generate the observed 

prevalence of HPV infection, and cohort studies’ observed mean durations of acute infection 

were used. The baseline no-screening model inserted the HPV type-specific proportions of 

cervical cancer incidence which, when combined, produced ~ 12/100,000 deaths annually. 

Screening was then introduced to the model and increased over 30 years to a high coverage of 

85% of women screened biannually. Shortening the period of chronic infection decreased the 

prevalence of infection; and since chronic infections are also infectious, HPV transmission was 

also reduced. Then, with vaccine introduction, vaccine-type HPV decreased. The rates of 

decrease differed due to each type’s different basic reproductive characteristics. Those with a 

lower reproductive rate are more sensitive to reductions in the duration of infection. 

Declines in mortality, LSIL and HSIL were charted, based on the same assumptions of 70% 

vaccine coverage among women and 85% coverage of biannual screening. Two scenarios were 

charted: a worst-case scenario where vaccinees stop screening (assuming they are protected) and 

a best-case scenario of rising reductions in cervical cancer cases and deaths due to screening, 

assuming lifelong vaccine protection.

For LSIL and HSIL combined, screening detection reduced cases per 100,000 screened women 

from ~350 to ~100-150. More analysis of the difference between high- and low-grade incidence 

is needed, which stemmed from the duration of naturally-acquired immunity or the difference 

between modeled and actual screening. More work also is needed to determine why the model’s 

assumptions produced a dramatic increase in the age-specific patterns of disease and prevalent 

lesions with older age. Adding 70% vaccination of men to the model produced additional 

decreases (~16%) in mortality among women, as the vaccination of men reduced the 

transmission of HPV from men to women. 

The impact of vaccine without boosters was charted, comparing no vaccination to lifelong and 

ten-year protection. The latter was divided between screened vaccinees and vaccinees that drop 

screening. With screening, the 10-year duration of protection group had a lesser reduction in 

mortality than those with presumed lifelong protection, but still a reduction. With 10-year 

duration of protection, vaccinees who drop out of screening had an increase in mortality 

compared to the scenario of no vaccination. 

A model was described which addressed the age of vaccination and use of catch-up programs. 

This deterministic model assumed 100% lifelong duration of naturally- and vaccine-derived 

protection, and compartmentalized women and men in a susceptible-vaccinated-immune 

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structure. Younger adults to age 44 years were stratified by age in weeks. The HPV transmission 

probability was estimated by comparing the model’s prevalence at different times to observed 

data for HPV-16 prevalence in the age groups. Sexual debut by a percentage of the population 

was presumed by a given age. 

For 70% vaccine coverage at ages 12, 15, and 18 years, the charted data indicated that 

vaccinating older age groups would have a more immediate impact on outcomes such as LSIL, 

HSIL, and cervical cancer. The more immediate impact arises because those in the older age 

groups are more likely to be sexually active, allowing vaccination to affect infection spread 

patterns immediately. But over time, vaccinating the younger population has a bigger impact; 

charted data showed 72% of HSIL cases prevented by 2050 with vaccination at age 12, versus 

67.5% at age 15 and 51.4% at age 18. With added vaccination of males, those proportional of 

cases prevented by 2050 rose to 84.9%, 79.9%, and 60%, respectively. The same pattern resulted 

for invasive cervical cancer cases, with vaccination at 12 providing the biggest impact over the 

long term. The same scale was seen with additional vaccination of males. 

Catch-up programs were also analyzed, defined as accomplishing coverage across the desired 

age groups immediately on program roll-out. In this case, the model assumed vaccination of all 

12-, 13-, 14-, and 15-year-olds, to reach a wider proportion of the sexually active population at 

once and to reduce infection spread, followed by vaccination of 12-year-olds thereafter. Again, 

the charted data showed the greater effect of vaccinating at the younger age, before the sexually 

active period, and a similar pattern was seen between HSIL and cervical cancer cases prevented.

Data were then graphed assuming a 12-year-old vaccination program, followed by catch-up 

vaccination programs at 3-, 6-, 9-, and 12-year intervals after vaccination. Diminishing returns 

were apparent with the increasing ages involved in the catch-up program, which was related to 

the proportion already infected when vaccinated. Catch-up vaccination done up to 6 years after 

initial vaccination at age 12 (i.e., age ~18, or even 21) would produce an effect, to prevent 

another ~12%-20% of cases, but there was little effect thereafter. The same pattern was true for 

cervical cancer cases. 

Finally, modeling the ages at vaccination assuming a ten-year duration of protection (and no 

booster) showed a tradeoff between the benefit of early vaccination, pre-sexual debut, versus the 

lost vaccine protection at the older and still sexually active ages. Nonetheless, vaccinating 12-

year-olds remained the best long-term strategy, although the benefit was not as large. Adding a 

booster again increased reductions in disease incidence.

Behavioral Issues Related to HPV Vaccination 

Presenter: Dr. Nicole Liddon, Division of STD Prevention 

 

Overview: Possible sexual behavioral issues resulting from HPV vaccines. 

Concerns have been expressed that an unintended consequence of HPV vaccine could be 

increased sexual risk behavior among vaccinated adolescents believing they are protected from 

an STD. That concern could influence vaccine implementation, if only due to parental fear of an 

increase in their child’s sexual risk, and pediatricians’ reactive reluctance to even raise the issue. 

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Behavioral disinhibition is defined as an increase in unsafe behaviors in response to perceptions 

of safety caused by introduction of a preventive or therapeutic intervention. This is not a new 

concept. There have been concerns about sexual disinhibition related to the use of anesthesia in 

childbirth and increased sex within marriage, and to increased sexual risk if penicillin were used 

to treat syphilis. Today, issues of needle exchange programs and condom use continue such 

discussions. 

YRBS data indicate that 7.4% percent of children from grade 9 through 12 have had sex before 

age 13; ~33% of 9th graders are sexually active, rising to ~66% by 12th grade. Of all 9th grade 

(not just those sexually active) 10.4%, have had four or more sex partners, as have 20.3% of all 

12th graders. Data from the National Survey of Family Growth are consistent with those findings. 

By age 15, ~25% of both males and females have had vaginal sex, rising to ~70% percent by age 

18 for females and 19 for males. Clearly, these data point to a need for vaccination in early 

adolescence, before sexual initiation and multiple sexual partners. 

The underlying hypothesis to the concern about disinhibition is that fear of HPV will motivate 

abstention from sex or at least prompt safer sex behaviors. Some of the factors influencing 

initiation of sexual activity were outlined. These indicated that the decision to have sex by 

adolescents is based on multiple and layered influences by family, peers and even school and 

community factors. It is rarely related to a single factor, such as HPV risk. In fact, NSFG data 

reveal that 15-19 year-old virgins’ fear of an STD (including HIV) was only cited by 10% 

percent of males and 7% of females as a reason not to have sex. 

Data from Merck's HPV vaccine clinical trials, emergency contraception, and condomavailability programs (CAP) were summarized to address the issue of sexual behavioral 

disinhibition among adolescents. 

• The Merck data of new male sex partners per person-year among North American 

women showed no increase in new sex partners per person-year after enrollment in the 

HPV vaccine trial, compared to self-reported activity beforehand. 

• Data from three randomized trials looking at young, sexually active women who attend 

healthcare clinics for reasons not related to emergency contraception, showed no 

differences between intervention (provided contraception) and control groups. 

• Data from the impact of CAPs includes both sexually active and sexually inactive U.S. 

adolescents. Overall, the studies show no significant change in the percentage of young 

people who have ever had sex, after having condoms available, or between schools that 

have CAPs and those without. 

Conclusion. Adolescent sexual behavior onset indicates early adolescence as the best time for 

HPV vaccine delivery. Various studies suggest that disinhibition will be unlikely to result. 

Sexual disinhibition is measurable and can be monitored, something being considered by the 

CDC and others (e.g., through NSFG and YRBS data collection). 

Options for ACIP Recommendation on HPV Vaccine

Presenter: Dr. Lauri Markowitz, Division of STD Prevention 

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Overview: Additional considerations by the HPV Working Group for vaccine 

recommendations, for discussion at the June ACIP meeting. 

The Working Group has focused on developing recommendations for use of the quadrivalent 

vaccine based on several assumptions: 1) the possible mid-2006 U.S. licensure of the 

quadrivalent vaccine for HPV-6, -11, -16, -18, and 2) its later licensure for use in males (pending 

data on efficacy for prevention of infection or disease in males). Also assumed is 3) that GSK’s 

bivalent HPV-16/18 vaccine will be licensed for use in females at a later date. 

A variety of background information needs to be considered for recommendations. This includes 

data on vaccine and clinical trials, burden of HPV related disease and epidemiology, sexual 

behavior, vaccine acceptability, programmatic issues and impact and cost effectiveness. 

Data from the clinical trials show that very high VE in 16-26 year-old females against the 

clinical trials’ vaccine-HPV type end points; protection has been shown through 21⁄2-31/2 years 

after dose 3; and the vaccine is safe, with only minor injection site pain reactions. 

Postvaccination seroconversion rates in 9-26 year-olds substantially exceed those achieved after 

natural infection, and are highest in those vaccinated at younger ages. Antibody titers decline 

over time after the third dose, but plateau by 18 months, remaining higher than those after natural 

infection for several years. 

Among the unknowns are a serologic correlate of protection (due to the trials’ high efficacy), the 

duration of protection or need for a booster, and missing data on efficacy among males. There 

are also knowledge gaps about HPV infection and natural history that might impact vaccination. 

Duration of protection is unknown for any new vaccine when first licensed. The quadrivalent 

HPV vaccine has some similarities to hepatitis B vaccine that may be instructive. Both are 

subunit vaccines with an alum adjuvant. Hepatitis B vaccine provides long-term protection, and 

although antibody titers wane in some individuals who receive hepatitis B vaccine, 

exposure/infection with hepatitis B usually does not result in chronic carriage or clinical disease. 

Direct comparisons are limited by the fact that hepatitis B is a systemic infection while HPV is 

mucosal or cutaneous. Questions have been raised concerning whether an anamnestic response

will protect individuals from persistent HPV infection and sequelae. Clearly follow-up studies 

are needed to monitor duration of protection from HPV vaccine . 

Other background information for recommendations also considered by the Working Group

includes was outlined. Vaccine acceptability is relatively high among providers and parents, but 

more for vaccination of older adolescents. Education about and recommendations from 

professional organizations could further acceptability. 

Cost Effectiveness – Models for impact and cost effectiveness of HPV vaccine are complicated 

due to the multiple HPV types, complicated natural history, and the long time between infection 

and health outcomes. The vaccine will not negate the need for cervical cancer screening, since 

HPV other than the vaccine types cause ~30% of cervical cancers. The models evaluated the 

impact of HPV vaccine in the setting of cervical cancer screening.

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Both the Markov and dynamic models show that high HPV vaccine coverage could prevent most 

vaccine-type-associated cancers and precursor lesions, reducing the 10,000 annual cervical 

cancers in the U.S. by ~70%. While the impact on cervical cancer will not be seen for many 

years, the impact on precursor lesions will be seen sooner. 

In the Markov models cost effectiveness has been approximately $24,000/QALY for bivalent 

HPV vaccine in females – with wide range in sensitivity analyses. In dynamic models, which 

include impact of herd immunity, the vaccine appears more cost effective. Work is ongoing 

using dynamic models to further evaluate the impact and cost effectiveness of quadrivalent 

vaccine. 

The Working Group’s possible recommendations for the ACIP to consider in June include: 

1. Recommendation for routine vaccination of females aged 11-12 years with three doses of 

quadrivalent HPV vaccine. The vaccination series can be started as young as nine years, 

at the discretion of the physician. (This depends on the FDA’s indication of the lower age 

of vaccination.) 

a. The rationale in support includes HPV infection’s high prevalence, the inability to 

target high-risk groups, and the modeling showing more impact with routine 

vaccination. 

b. This strategy would result in vaccination of more females before sexual debut, 

resulting in greater prevention impact. Implementation of a three-dose schedule at 

this age is also aided by the fact that other vaccines are recommended at this age 

and a young adolescent healthcare visit is recommended by professional 

organizations. 

c. There is no evidence of waning immunity and ongoing studies will monitor 

duration. 

2. Upon vaccine introduction, there will be unvaccinated older females who could benefit 

from the vaccine, and FDA approval through age 26 years is expected. The options to 

vaccinate 13-26 year-olds include: 

a. Vaccination of all females aged 13-26 years who are not been previously 

vaccinated.

b. Permissive recommendation for all age groups with a specific recommendation 

for a more limited age range. 

c. Further modeling will be done and discussed for this age group. 

3. Vaccination of males. It is expected that licensure will be at a later date, when there are 

efficacy data in males. Possible initial ACIP statement wording could be similar to, 

“HPV vaccine is not licensed for use in males. Studies in males are under way and results 

are awaited.” 

The Working Group will continue discussion of the quadrivalent vaccine recommendation 

options, and modify them as needed after the FDA licensure. The draft recommendations and 

options will be circulated before the June ACIP meeting. Future discussions will develop 

recommendations for the bivalent HPV vaccine. 

Discussion by the committee of the HPV presentations included: 

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• The main arguments against recommendations to immunize to age 26 involved feasibility 

more than any other issue (e.g., to catch up) and still-incomplete cost effectiveness data.

• Dr. Lieu asked about the sensitivity of the CE analysis to the cost of vaccine, and how 

likely the analysis’ costs will match the vaccine cost. Dr. Chessen answered that the 

analysis is sensitive to vaccine cost, since that is a large part of the cost per QALY. In 

some cases, doubling the vaccine cost more than doubles the cost per QALY. Dr. 

Feinberg reported that Merck has not yet determined the vaccine’s cost. But relevant 

data are continuing to emerge and are expected to make the true value of the vaccine 

apparent. The latter needs to be stated to provide the context when the vaccine price is 

announced. 

• Dr. Hull observed that low SES, undereducated women will not be vaccinated without a 

mandate, and they are the same group that disproportionately dies from cervical cancer. 

He asked what effect those factors had on the models’ highest risk populations. Dr. 

Chessen responded that that issue has less impact in a CE analysis, because many of the 

vaccine’s benefits involve reducing the follow-up costs after screening. But it would 

affect cervical cancer incidence, and he hoped to add that into the analysis later. 

• Dr. Chessen confirmed for Dr. Finger that the averted medical costs were included in the 

CE analyses. Some of the papers did not provide a breakdown of the benefits, but he 

offered to get that from the modelers. 

• Dr. Gall supported beginning the vaccine’s use at age 11 or 12, but added that 

vaccination for females aged 13-26 who were not previously vaccinated is also critical. 

ACOG could not support a recommendation for this vaccine only for pediatric use. Just 

one reason for that was that solely pediatric use would provide no impact on cancer 

prevention for ~25 years. 

• Dr. Sam Katz observed that almost all the studies presented related to the U.S., and asked 

what modeling had been done for resource poor countries without cancer screening. Dr. 

Garnett reported a lot of work on that, particularly by Dr. Goldie, under a grant from the 

Gates Foundation and the WHO. She is collecting data and studying the vaccine’s 

impact in India, Latin America and other resource-poor areas. The results for the U.S. 

were presented “because that is where we are.”

• Dr. Traenor commended this as the most informative session he had ever attended in 

discussing the pro’s and con’s of a vaccine. He asked what the assumptions were, in the 

scenarios of low vaccination rates in women, about the VE of vaccinating men. Dr. 

Garnett reported that the assumption was of similar effectiveness against acute infection 

in men as seen in women ─ a very high efficacy.

• Dr. Pickering asked about vaccine availability. Dr. Feinberg reported that Merck had 

invested significant resources to ensure its availability for all indicated cohorts in the 

label for the first years of use. Dr. Monteyne reported the same as true for GSK. 

• Bridging . Dr. Martin Myers asked FDA’s opinion of the correlation of immunogenicity 

between the 9-15 year-old female age group to that in males, as a surrogate marker. Dr. 

Baylor responded that it was too early in this vaccine application’s review to comment 

on that. Dr. Powell asked why the bridging data could be applied to young adolescent 

females but not males. 

• Dr. Markowitz responded that the 9-15 year old females could be bridged to VE in older 

females, but there was no such parallel group for the boys. 

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• Dr. Barr added, from Merck’s perspective, that the 100% VE, slightly higher 

immunogenicity found in boys, and the same type of hair-bearing, keratinized skin 

around the genitalia of both sexes, supported male vaccination. That also would provide 

the benefits of herd immunity to controlling infection. 

• Dr. Peggy Reynolds demurred, noting that not only is efficacy not shown for males, but 

also that females are protected from cervical cancer by transudated IgG. 

• Dr. Dubin cautioned that the genital herpes vaccine trial showed differences in genderbased efficacy, despite the similar distribution of genital herpes lesions in men and 

women to that of genital wart lesions. That could be applicable to the questions about the 

relevance of bridging. 

• But Dr. Barr disagreed, calling that speculation. He added that the objective is not only to 

prevent cervical cancer, but RRP, genital warts (for which the vaccine is 100% effective 

on women’s external genitalia), and other cancer burdens that HPV can cause. Although 

the organs are different, the skin is the same, as is the natural history, HPV types, 

treatment and efficacy. He urged vaccination of males to avoid the limitations of a 

gender-specific policy and to broaden the vaccine’s availability to all. 

• Dr. Temte asked about cost effectiveness considering the incremental costs with male 

vaccination added, and whether that would make it so expensive as to prevent a 

recommendation. Dr. Chesson could only report that the range of costs per QALY is 

great across the only two studies that address this question. CDC is trying to figure out 

now why that is. 

• Dr. Schuchat noted that the models assumed the stability of other HPV types. She asked 

if there was any reason for concern about replacement types, particularly as regards the 

herd immunity being modeled. Dr. Garnett reported that was included in the analysis. 

The concerns were that removing the progress to disease can invite replacement by other 

types; and that this could create a niche for the other types by removing the natural cross 

immunity. That will be studied in Finland. But evolutionarily speaking, the HPV types 

are ~10% different in genotype, and 2% different even within types, making them fairly 

stable. This is an important issue. Additional immunity created by the vaccines, which is 

not conveyed by natural infection, is also possible and being studied. Dr. Barr added that 

the HPV-16 vaccine trial showed comparable disease rates caused by the four types. He 

also noted that women infected with one type are at higher risk for another and thought a 

replacement phenomenon to be highly unlikely. 

• Dr. Renee Jenkins, of the National Medical Association, pointed out that access to this 

vaccine for eligible children would be through the VFC program, which is already under 

strain. Dr. Lance Rodewald reassured her, though, that by statute, VFC coverage is 

mandatory spending and the funding will be available. However, the Section 317 

funding is discretionary, and more of a concern. 

 

PUBLIC COMMENT

Dr. Bobbi Gostout, Associate Professor at the Mayo Clinic, attended to represent the Society of 

Gynecologic Oncologists. She had no vaccine-related conflicts to declare. She stated the 

importance that the ACIP hear from physicians serving the women who still develop cervical 

cancer, even in highly screened populations. There are no easy solutions; some women cannot 

or will not avail themselves of care; some do not understand the importance of screening; and 

some rely on a Pap test result that turns out to be a false negative. HPV vaccine provides hope 

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for all those categories and most promisingly, it would reduce the endocervical cancers that are 

missed by current screening, as well as the >90% caused by HPV-16 and -18. Those who 

survive cervical cancer often cannot have children thereafter. It is so disturbing to see these 

cases, knowing that the field is so close to eliminating the disease. She put the Society of 

Gynecological Oncologists on record at this meeting in support of action by federal agencies to 

approve and license the vaccine as soon as possible and to disseminate it as broadly as possible. 

The SGO supported maximum vaccination of females and, as the science supports it, of males, 

and urged the ACIP to recommend that the VFC program include this vaccine. 

Ms. Chris Armenderez, a psychologist from Minnesota, is also a patient of Dr. Gostout who 

treated her for invasive cervical cancer. For years, her Pap test results were returned as Class 2. 

noting “possible cellular inflammation,” then accelerated to Class 3+. After a miscarriage that 

occurred about six month before her diagnosis, she had fairly constant bleeding, including after 

sex. An endometrial biopsy found severely abnormal cells and she had a D&C, after which her 

cancer was diagnosed. Before her surgery, she sat up all night holding her sleeping 3-year old 

son, mourning that if she died early, he would not remember her. Her surgery was successful. 

She stressed the tragedy that women without access to medical care die of this, and supported 

implementation of the vaccine so that no one else would have to go through her experience. 

Dr. Carolyn Runowicz, President of the American Cancer Society, also strongly supported the 

ACIP’s approval of HPV vaccine. Not only is it historic as the first cancer vaccine, but it can 

help address cancer’s disparity, which disproportionately affects the underserved, uninsured, 

underscreened, and racial and ethnic minorities. If this vaccine is widely implemented 

throughout the school system as other vaccines are, that disparity can be affected for cervical 

cancer. The vaccine offers the power and the opportunity to prevent this disease. 

Ms. Amelia Toper, a survivor of cervical cancer, urged the ACIP to make the vaccine available 

to all individuals, with no age limit. She is a nurse and married with two children, one 18. 

Although she always followed health guidelines such as annual Pap screening, her cancer was 

diagnosed in stage 1B. It was removed, but she still worries about recurrence and for her 

daughter. That angers her, because this is a preventable disease. Despite her post-operative 

discomfort, she drove 11⁄2 hours to urge the vaccine’s recommendation by ACIP. She attended to 

speak, to protect her daughter and other women. An ACIP recommendation will extend HPV 

vaccine’s availability to all women and every child, male and female. 

Ms. Susan Crosby is the President and Executive Director of Women in Government. A national, 

nonpartisan organization for female state legislators, the WIG works with the legislators to 

provide information helpful to making difficult policy issues. In 2004, 44 states developed 

cervical cancer prevention legislation. To date, 37 have passed it, to learn its causes, incidence, 

mortality, and what each state can do to eliminate cervical cancer. She asked the ACIP to help 

these women legislators by recommending that the vaccine be made available to all, regardless 

of their socioeconomic status. 

Ms. Moira Gaul, a policy analyst for the Family Research Council, welcomed the vaccine’s 

potential for improving health and preventing deaths. She thanked Merck and GSK for meeting 

with the FRC to explain their goals for marketing this vaccine. The FRC will follow the 

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vaccine’s experience to see if it is safe and effective for all, and has found that to be very 

encouraging so far. The FRC also will follow the activities of the pharmaceutical companies, the 

federal and state governments, and the medical community as the vaccines are released, 

especially to determine if there is any impact on sexual activity. They are very concerned that 

information be distributed to public health, physicians and parents, that HPV will not prevent 

other STDs, even other HPV types that cause cancer. Recognizing the recent epidemiological 

studies’ finding that the vaccine is most effective at earlier ages, she cautioned the health care 

community to clearly convey that only abstaining from sexual contact protects from STDs. But 

since HPV also can come from sexual abuse/assault, or marrying someone infected, the vaccine 

is a benefit. Since parents should decide about matters of their children’s health, the FRC 

strongly opposed any mandate, including school entry, since HPV is not easily transmitted. 

Health care providers should discuss the full range of issues affecting health. Counseling on risk 

elimination strategies to prevent STDs should be developed, to match the risk elimination 

messages for tobacco, drug and alcohol abuse. The best primary prevention is to limit sexual 

activity to a single, life-long monogamous relationship, thereby avoiding the physical and 

psychological effects of STDs. 

ROTAVIRUS VACCINE

Data Review, Rotavirus Efficacy and Safety Trial (REST)

Presenter: Dr. Penny Heaton, Merck 

Overview: Overview of Phase III clinical trial study design; safety and efficacy data 

supporting licensure of Merck’s pentavalent human bovine reassortant rotavirus vaccine 

(PRV). 

The FDA approved the safety and efficacy data of Merck’s Phase III trial of a pentavalent human 

bovine reassortant rotavirus vaccine (PRV) and licensed it on February 3, 2006. PRV is an 

orally administered vaccine that is suspended in a liquid buffer stabilizer. The buffer protects the 

vaccine from gastric acid and the stabilizer allows refrigerated storage with a 24-month shelf life. 

It is easily administered directly from the tube to the infant, and has a three-dose regimen 

compatible with the childhood schedule. The trials administered the first dose at age 6-12 

weeks, followed by two more doses at 1-2 month intervals on the 2, 4, 6-month schedule and the 

2-, 3-, 4-month schedule. The formulation contains five human bovine reassortants, including the 

human G1, G2, G3, G4, and P1(8), which constitute >90% of the rotavirus strains in the U.S. and 

worldwide, and bovine G6 and P7. 

The PRV development program was outlined, from the vaccine technology’s licensure in the 

early 1990s through three Phase II studies and three Phase III studies: efficacy and safety trial 

(006), dose-confirmation efficacy study (007), and lot consistency study (009). 

Evaluations. The efficacy evaluated in the Phase III studies were VE to prevent rotavirus acute 

gastroenteritis caused by the vaccine serotypes (G1-4; non-G1-4 strains containing P1; and VE to 

reduce healthcare encounters for rotavirus gastroenteritis, including hospitalizations, emergency 

department (ED) visits, and physician office visits. Other than vaccine immunogenicity, the 

study explored antibody responses to concomitantly administered other licensed vaccines, and 

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safety relative to serious adverse events (AE), including intussusception. Other AEs of special 

clinical interest (for any live rotavirus vaccine) were fever, vomiting, and diarrhea.

Study design. The Phase III trials involved 71,799 subjects, 36,000 of whom received PRV and 

35,799 received a placebo. The age at first dose was 6-12 weeks and the next two doses were 

administered every 4-10 weeks, year-round. Case definitions were developed that included 

ELISA confirmation for rotavirus gastroenteritis and radiographic, surgical, or autopsy diagnosis 

for intussusception. Active surveillance followed every infant for safety and healthcare 

encounters for rotavirus gastroenteritis. The parents were called at weeks 1, 2, and 6 after 

vaccination and then every six weeks thereafter, up to a year after enrollment. Extra calls were 

made every two weeks during rotavirus season, and children vaccinated during the season were 

followed through that and the next full rotavirus season. 

Vaccine efficacy results. VE against G1-4 rotavirus gastroenteritis was:

• 73.8% against any rotavirus disease, 98% against severe disease. 

• Reduction in hospitalizations: 95.8%; in ED visits, 93.7%, in office visits, 86%. 

• VE ranged from 68-82% with overlapping confidence intervals, and did not vary 

according to infant feeding status (i.e., breast fed, breast and formula fed, etc.) 

• VE in premature infants (N=2000) of gestational age ranging from 30-35 weeks was 

similar to that of the overall population, at 70% against any severity of rotavirus 

gastroenteritis.

Immunogenicity. The statistical criterion for demonstrating non-inferiority for concomitantly 

administered DT, IPV, Hib, and Hep B was ≤10 percentage points decrease among PRV versus 

placebo recipients, for the proportion who achieve seroprotection (95% CI). The criterion for 

pertussis and pneumococcus: ≤2-fold decrease among PRV versus placebo recipients for the 

ratio of GMT (95% CI). The analysis compared antibody responses to the licensed vaccines coadministered with PRV versus given with placebo, for: 

1. Three doses of DTaP and pneumococcal conjugate vaccine, measuring GMTs ~1 month 

after the third dose (at age ~7-8 months) 

2. Two doses of COMVAX® (Hib/Hep B) and IPV, measuring GMT at ~5 to 6 months of 

age.

Results. The statistical criteria for diphtheria, tetanus, IPV, Hib, hep B, and the pneumococcal 

conjugate serotypes were met. For pertussis, the statistical criteria for toxoid and FHA were met, 

but not for pertactin. No cause for that was found. Retesting mirrored the original results, but for 

additional tested subjects and the combined sample, the criteria for all three compartments were 

met. There still is no explanation for the initial pertactin failure, but the reanalysis showed that 

the pre-immunization titers were not a factor.

Conclusions. The data support concomitant administration of PRV with the already-licensed 

childhood vaccines. The clinical significance of the original lower pertactin titers remains 

unclear. Additional testing and/or another study to confirm the reanalysis’ favorable results is 

being considered. Data show that two-component vaccines, particularly in post licensure 

effectiveness studies, show protection against pertussis that is similar to that of multi-component 

vaccines.

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Safety results for intussusception. In all, REST had 35 investigator-diagnosed cases of 

intussusception. Two cases were negatively adjudicated and one case could not be adjudicated 

due to malfunctioning equipment; all were in the placebo group. Thirty-two cases were 

positively adjudicated; of those, four cases occurred after the child completed the study and 

again, they were all in the placebo group. Of 28 cases identified in the year follow-up after a 

dose, 11 occurred with 42 days of the dose, six in the vaccine group and five in the placebo 

group. Seventeen cases, seven in the vaccine group and ten in the placebo group, occurred 

outside of that 42-day period but within the one-year safety follow up. 

Intussusception case intervals were charted by dose and by day post-dose. The relative risk for 

dose one was 0.9; that for the 42-day period after any dose was 1.2 (1.6 if adjusted for 

multiplicity, in a 95% CI of 0.3 to 5.0). The data charted by day showed a sporadic distribution 

of the cases. There was no clustering of vaccine cases without a similar cluster of placebo cases, 

and none occurred in the two-week period after Dose 1, the period of greatest intussusception 

risk with Merck’s former rotavirus vaccine, RotaShield.® 

 

AEs of special interest. Fever after each of the three doses was similar in both the vaccine and 

placebo groups. For vomiting and diarrhea, the small differences between vaccine and placebo 

groups were small (1.3%) but statistically significant. However, the vast majority of these cases 

were characterized as mild by the physician. 

 

Conclusion. PRV is efficacious against rotavirus gastroenteritis of any severity and highly 

efficacious against severe disease. It reduced healthcare encounters for rotavirus gastroenteritis 

by 96% for hospitalizations, 93% for ED visits, and 86% for physician office visits. 

Concomitant use data indicate the PRV can be co-administered with DTaP, IPV, Hib, hep B, and 

pneumococcal conjugate vaccine. PRV is well tolerated with respect to all adverse experiences, 

including intussusception with some mild, small increases in mild diarrhea and vomiting. 

Review of Cost Effectiveness Data

Presenter: Dr. Mark Widdowson, National Center for Infectious Diseases (NCID) 

Overview: Updated, expanded results of the cost-effectiveness analysis presented to 

ACIP in October 2005. 

This cost effective analysis was done with a probabilistic model in which a fictitious 100,000 

children were followed from birth to age 59 months to estimate the cumulative number of 

different rotavirus disease outcomes in that period. The same number of outcomes were 

calculated for this cohort, but vaccinated, at 2, 4, and 6 months. Medical and nonmedical costs 

of each outcome type were estimated, including the cost of the vaccine program and adverse 

reactions. The cost effective ratio was calculated from the healthcare-payer perspective (medical 

costs) and the societal perspective (both medical and nonmedical costs), for cases averted and 

life-years saved. The resulting distributions for each input to the model were then combined to an 

output distribution, and all distributions were plotted for a median and a 95th percentile. 

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Disease burden inputs assumed at least one episode of clinical rotavirus disease per child by age 

59 months, among 75% of the U.S. children (3 million). NCHS provided data on rotaviruscaused diarrhea outcomes which required healthcare over a ten-year period. That was multiplied 

by a published fraction for rotavirus, to arrive at the annual number of rotavirus disease 

outcomes per year. Published RV mortality data were used to calculate annual rotavirus deaths. 

Rotavirus outcomes ranged from death, hospitalization, hospital outpatient, ED and physician 

office visits, and care at home, for >3 million cases of rotavirus. The large (5 million enrollees) 

MarketScan database supplied data for four years of medical costs, which were translated to 

2004 dollars and then discounted by 3% for the social and healthcare perspectives. The median 

cost calculated for hospitalization (median of 2 days), for example, was $2962, ranging from 

$1181 at the 5th percentile to $7426 at the 95th percentile.

Nonmedical costs included days lost from work to care for a sick child ($118/day), travel for 

health care, extra diapers, special food, child care costs, and for mortality, lifetime productivity 

lost. The data used for vaccine efficacy outcomes (the same five listed above for rotavirus 

outcome) were adapted from the Rotateq® trial, published in the January New England Journal.

This trial used a range of efficacy measures, from 65 % for mild diarrhea to 90% against 

hospitalization and death. 

The cost effective ratio was calculated for several program costs: dose of oral RV vaccine, its 

administration, hospitalization for intussusception (1:50,000 vaccinees, which added 10 cents to 

the total vaccination cost per child), and outpatient workup for non-intussusception adverse 

events (an extra 15 cents per child vaccinated). In the absence of a vaccine price, a cost range of 

$10-$80 was used, plus $10 per dose to administer it, resulting in a range of $30-$240 per child. 

Analysis results for cost effective ratios per case of rotavirus averted were charted, from the 

healthcare perspective and the societal perspective. From the healthcare perspective, the 

breakeven point was a total cost of $33/dose; anything less would be cost saving. From $33-

$66, the vaccine program probably would be cost effective; from $66-$143, cost effectiveness 

would be unlikely, and above $143, it would not be cost effective. If administration costs are 

removed, the $66 to vaccinate becomes ~$12/dose. With Merck’s $62.50 published list price for 

the new rotavirus vaccine translating to a total cost per vaccinee of ~$217, the rotavirus vaccine 

would not be cost effective from a healthcare perspective. 

From the societal perspective, breakeven cost is $107 total cost per dose. From $107 to $156, 

the program would likely be cost saving, but unlikely to be so from $156 to $238; and after $238, 

it would not be cost saving. The total $107 cost translates to $42 per dose, which again makes 

Merck’s $62.50 price unlikely to be cost saving from a societal perspective. But there was also a 

20% chance that it may be cost saving at $62.50/dose. 

Charted by life-year saved, the breakeven points mirror those for each case averted. But the 

rarity of deaths prevented by rotavirus vaccination makes the potential costs per life-year saved 

much greater, at $400,000 per life-year saved versus $400 per case averted. A separate 

sensitivity analysis was done to account for 50% of days lost from work, subtracting that from 

the base-case estimate. Increasing the days off work made the vaccine program more cost 

This document has been archived for historical purposes.
effective and conversely, less cost effective with less days off work. The breakeven point, 

including extra days off work, was $52 per dose, still outside the Merck price. 

The cost effective ratios for different outcomes at $62.50/dose were charted from the healthcare 

perspective: $470,729 per life-year saved and $336 per case averted. From a societal 

perspective, it would $197,190 per life-year saved and $138 per case averted. Results of a 

sensitivity analysis of the model’s inputs were charted, showing the most important to be the cost 

per hospitalization and per ED visit.

Reduced morbidity in the U.S. due to a vaccine program for the 4 million birth cohort (July 

2004) was charted, assuming 70% coverage for the full three doses by age 6 months, and 25% 

coverage for only one or two doses (half the efficacy). The program would reduce events 

(hospitalizations, home care, ED/office visits, etc.) by an average of 51%. There would be more 

reduction of hospitalizations and ED visits than of home care needed, because of the increased 

efficacy for more severe outcomes. From the medical perspective, at Merck’s price, the 

program’s medical costs would be $514 million. But it also would save a substantial nonmedical 

cost total of $300 million, meaning a final cost from the societal perspective of only $250 million 

at $62.50 per dose and the same coverage rates. 

It is important to remember that vaccines are not necessarily cost saving. A chart demonstrated 

that the newer vaccines are less cost effective than the older ones. One dose of varicella and the 

hepatitis B vaccine provide savings, while pneumococcal, meningococcal, pertussis and rotavirus 

vaccines incur net costs, from both a case saved and QALY saved perspective. 

Among the analysis’s limitations were that the vaccine’s true cost will probably be less than 

$62.50 for the VFC program, and that private contracts introduce another variable. Initial 

coverage levels also will likely be much lower thank 70%, which is the DTaP level. While that 

would not affect the cost effective ratio, it would affect the overall net cost of savings of a 

vaccine program. Finally, the analysis does not include the psychological costs of anxiety about 

a sick child or about adverse reactions. 

Physician/Provider Surveys on Rotavirus Vaccine Use

Presenter: Dr. Alison Kempe, University of Colorado 

Overview: Rapid turnaround national survey done by CDC of practitioners’ attitudes 

and beliefs about rotavirus vaccine use. 

This national survey sought to determine pediatricians’ knowledge and attitudes about rotavirus 

disease, their intentions about recommending a new rotavirus vaccine, and perceived barriers to 

rotavirus vaccination. 

Survey methods were outlined. It was conducted in a sentinel physician network that was 

randomly recruited from AAP membership, but designed to be representative of the AAP 

membership overall and of the region of the country, practice location (urban, inner city or not; 

suburban, or rural), and setting (private, managed care, hospital-based, etc.) A panel of 

pediatricians developed the survey, which was administered by mail or e-mail in January and 

This document has been archived for historical purposes.
February 2006. It is still not completed. 

Preliminary results. The response rate at the time of the interim analysis was 66%. Respondents 

and nonrespondents were similar in terms of region, practice setting or location; 55% were male, 

45% female; 65% of respondents had >50% of their patients who were insured; 78% percent 

participated in the VFC program. 

• Perceived rotavirus burden: 1) Most common cause of infectious diarrhea in children 

aged <2 years: 55% strongly agreed; 30% somewhat agreed; 2) most frequent cause of 

severe diarrheal disease in children aged <2 years: 82% strongly agreed; 3) need for a 

safe and effective rotavirus vaccine in the U.S., 51% strongly agreed, 37% somewhat 

agreed.

• Experience with RotaShield:® All the respondents were aware of the problems associated 

with RotaShield® before its withdrawal from the market, by: 1) administration: 53% 

administered it routinely; 9% intermittently; 38% had not administered it; 3) experience 

of intussusception: 12% had patients or knew of patients who had intussusception 

suspected of an association with RotaShield.® 4) plans to discuss the RotaShield®-

intussusception association with patients when discussing the new vaccine: 50% would 

routinely discuss it; 32% would do so only if it was raised by the parents; 6% would not 

discuss it; 11% were unsure. 

• Intentions to recommend the new vaccine if ACIP and AAP recommend it for routine 

versus permissive use: 1) Routine use: 50% would strongly recommend it; 34% would 

recommend; 11% would inform but not recommend; 1% would recommend against it. 

2) Permissive use: 33% would strongly recommend, 43% would recommend but not 

strongly, 19% would inform but not recommend, and 1% would recommend against. 

• Speed to implement vaccine use if ACIP/AAP recommended routine use: 51% would 

begin within six months of the recommendation; 28%, 6-12 months; 7%, 1-2 years; 1%, 

2 years. Another 14% were unsure. 

• Reasons to wait >6 months: 1) insurance coverage: 90%; ensure no vaccine side effects: 

81%; adequate vaccine supplies: 65%; see if other providers use the vaccine: 36%; see if 

parents accept the vaccine: 20%. 

• Barriers to giving rotavirus vaccine: 1) failure of some insurance companies to cover 

vaccination: definitely, 51%; somewhat of a barrier, 28%; 2) lack of adequate 

reimbursement for vaccination: definitely a barrier, 42%; somewhat a barrier, 32%; 3) 

parents' reluctance due to RotaShield® withdrawal: definitely a barrier, 30%; somewhat 

a barrier, 42%.

• Physicians’ concerns about rotavirus vaccine safety: 1) definitely a barrier, 21%; 

somewhat a barrier, 26%; 2) upfront vaccine purchase costs to the practice: definitely a 

barrier, 21%, somewhat a barrier, 27%; 3) concern about obtaining adequate supplies: 

definitely a barrier: 20%, somewhat a barrier, 33%.

• Definite barriers to rotavirus vaccination by ≤15% of respondents: parental concern about 

vaccine safety in general, 15%; parents thinking rotavirus vaccine is unnecessary, 12%; 

respondent concerns about adding another vaccine to an overloaded vaccine schedule, 

9%; respondents' belief that rotavirus was not a severe disease requiring vaccination, 5%; 

time needed to discuss vaccine safety with parents, 4%; general administrative burden to 

the practice, 3%. 

This document has been archived for historical purposes.
The survey data’s limitations include potential selection bias, despite efforts to build a study 

population representative of the AAP or the AMA, and that the survey measures the intent to 

vaccinate rather than what physicians are actually going to do. 

Conclusion. Most pediatricians (88%) surveyed believed there was a need for a rotavirus 

vaccine in the U.S. If a new rotavirus vaccine were recommended for routine use, 83% would 

recommend it, 50% of them strongly. With permissive use, fewer would recommend ─ 77% 

overall and 33% strongly. A majority, 51%, would begin using vaccine within six months of 

ACIP/AAP recommendations. Barriers anticipated by respondents included the lack of broad 

coverage by insurance companies, lack of adequate reimbursement to physicians giving this 

vaccine, and parental reluctance to vaccinate because of withdrawal of the prior rotavirus 

vaccine. When discussing new rotavirus vaccine with parents, many would discuss the 

association with prior vaccine and intussusception, either routinely or if it was raised up by the 

parents. 

Post-licensure Surveillance Plans

Presenter: Dr. Penina Haber, Office of the Chief Science Officer, CDC

The main tools for post-licensure safety monitoring are the Vaccine Adverse Event Reporting 

System (VAERS), a national passive surveillance system for reporting vaccine adverse events, 

and the Vaccine Safety Datalink (VSD), a collaboration between CDC and eight large U.S. 

health maintenance organizations with an annual enrolled birth cohort of >90,000. 

VAERS is a voluntary nationwide reporting system able to detect previously unrecognized or 

rare reactions. Monitoring for those will be done by CDC and FDA, reviewing daily reports and 

alerts of all serious adverse events and other medically important conditions. The VAERS main 

focus in this case will be on intussusception and suspected intussusception, any reports of which 

will prompt immediate follow-up, and other serious gastrointestinal outcomes. A VAERS 

analysis of serious reports includes radiology, surgery, or autopsy information and medical

records confirmation. The Brighton case definition for intussusception will be applied to verify 

suspected reports. The reports will be graded and then compared to the background rates 

obtained from the VSD data. 

The VSD’s advantages for vaccine safety research are its access to a large and well-defined 

population, with computerized linkable administrative databases to support controlled 

population-based studies. The VSD rapid-cycle (real-time) analysis for Rotateq will monitor for 

possible increased risk of intussusception, and evaluate other prespecified conditions and 

associations identified from VAERS and from the manufacturer’s Phase IV studies. 

The post-licensure study will include infants aged 0-12 months who received the Rotateq® 

vaccine, followed for 40 days after vaccination. Automated outcomes data and chart validation 

will be in the analysis, and sequential statistical testing will compare rates of intussusception and 

other conditions seen after Rotateq,® to expected rates. 

Merck’s Pos-tlicensure Monitoring Plans

Presenter: Dr. Chris Mast, Merck 

This document has been archived for historical purposes.
Merck is implementing a three-phase or three-component plan for comprehensive 

pharmacovigilance to monitor vaccine safety: 1) maintenance of a large safety database of 

ongoing and future clinical studies of Rotateq® among >71,000 subjects, to monitor the safety of 

this product; 2) two pharmacovigilance activities, one a prospective population-based study 

assessing intussusception and general Rotateq® safety, and the other enhanced passive reporting 

through telephone follow-up of all intussusception cases and expedited case reporting to the 

FDA. FDA also will be apprised of all adverse events monthly, in addition to Merck’s quarterly 

reporting. And, 3) Merck will coordinate and collaborate with CDC and the FDA on these 

respective pharmacovigilance activities.

Merck’s active surveillance plans, approved by the FDA, were summarized. The prospective 

surveillance study will explore both intussusception and general safety in the same study 

population. The study population is a large insured population, separate and complementary to 

the CDC/VSD study. In that, Merck will evaluate all infants (~44,000) receiving Rotateq® (onor off-label) during the study period. Safety will be assessed for 30 days after each dose, as well 

as alternate intervals for the secondary analysis. 

The post-licensure study will compare the incidence of intussusception among vaccinees to the 

background rate. The latter will be examined in a baseline study before licensure, to confirm the 

study’s operating statistical assumptions. A sequential design similar to Dr. Haber’s description 

will assess intussusception cases as they occur and continuously monitor during the study period. 

One objective to be explored is the use of unvaccinated concurrent controls if potential 

confounding factors can be controlled. 

Safety will be assessed descriptively by recording adverse experiences among infants who 

received Rotateq® in periods after vaccination. Analytical assessment of general short-term 

vaccine safety will compare post-Rotateq® vaccination adverse events with two control periods. 

In one, vaccinees will be their own control group, and the other is a historical cohort. All adverse 

events resulting in hospitalization or ED visits during the study period will be captured. This 

method has been used for other vaccines, and the results were published. 

Discussion included: 

• Dr. Lieu raised the cost effective analysis results of $178,000 per life year saved, and 

$138 per case averted. Another analysis that would be helpful, would be to go on to 

calculate dollars per QALY. She had quickly calculated a net societal cost, after 

deducting work loss, of ~$250 million per year and 1.5 million cases averted. She 

calculated further that if about a day of life is traded to avoid a case of rotavirus, that the 

vaccine would appear cost effective at $50,000 per QALY saved. Dr. Widdowson 

reported a life year saved analysis as briefly discussed but not done, because the 

relatively brief rotavirus episodes would not greatly affect the subsequent QALYs. 

However, that could be estimated. 

• Dr. Campbell asked what the duration of the vomiting or diarrhea was among the 15%-

25% of vaccine recipients, so as to understand the impact on parents’ time lost from 

work. Dr. Heaton responded that these episodes, being described as mild, would typically 

only last 1-2 days. 

This document has been archived for historical purposes.
• Dr. Kempe conveyed Merck’s own surprise that the physicians asked about Rotateq were 

so generally positive, although they tend to be so about new vaccines in general. They 

seemed to view Rotateq as a new vaccine

• Dr. Morse asked if parents had been surveyed as well, and if so, if they shared the 

pediatricians’ concerns about safety. Dr. Jim Alexander, of NIP’s health communications 

staff, reported that CDC is doing key informant interviews and focus groups of parents, 

especially young parents likely to have, or about to have young children, to assess their 

attitudes about new vaccines. 

Rotavirus Vaccine Working Group Draft Proposed Recommendations 

Presenter: Dr. Umesh Parashar, NCID

The recommendation options for vaccine use in general were for routine or universal use, 

permissive, or a targeted strategy to high-risk groups. Considerations discussed by the Working 

Group included: 

• Burden of rotavirus illness in the U.S. in children aged ≤5 years, ~70% (2.7 million) 

children will have an episode of rotavirus gastroenteritis, resulting in >200,000 ED visits, 

>400,000 outpatient visits, 55,000-70,000 hospitalizations, and 20-60 deaths annually. 

Charted cumulative hospitalization rates showed 90% due to rotavirus by age 2 years. 

• High-risk groups for severe RV disease include infants with low birth weight, those born 

to young mothers, and those socially disadvantaged. But these groups comprise only a 

fraction of overall severe RV cases, so a targeted vaccination strategy would not 

effectively reduce severe rotavirus disease. Routine or universal immunization of infants 

with three doses of this vaccine given at 2, 4, and 6 months of age was chosen as the 

optimum strategy. Dose 1 would be given from 6-12 weeks of age, as done in the 

clinical trial. That is supported by available safety data. All three vaccinations should be 

done by 32 weeks of age, with at least a 4-10 week interval between doses. 

• NIS data show an 88% uptake of the first DTP dose by 12 weeks of age, then rising in a 

slow plateau to 98% by age one. So, although having the strict cutoff for 6-12 weeks of 

age would potentially reduce vaccine coverage by 10%, the Working Group opted to 

follow the age period supported by safety data from the clinical trial, at least in the initial 

years of the immunization program until more data are available through post marketing 

surveillance. 

• The vaccine can be administered to infants with transient mild illnesses and can be coadministered with other vaccines given at 2, 4, 6 months of age. 

• There are two contraindications proposed by the working group: T- or B-cell deficiency 

(including infants of HIV-positive mothers, unless the infant is clearly uninfected), since 

this is a live viral vaccine. The second is serious allergy to any vaccine component or to 

a previous dose of the vaccine. 

• Precautions are stated for infants with moderate or severe acute gastroenteritis at the time 

of vaccination and infants with moderate or severe febrile illness. In both cases, 

vaccination should be delayed to recovery, unless the pediatrician fears that the child will 

not return for vaccination. Infants with pre-existing chronic gastrointestinal disease can 

be vaccinated, since the risks of the disease are greater. There is no association of this 

vaccine to intussusception, but infants who have had a prior episode of intussusception 

should not receive this vaccine. Premature infants can be immunized if they are at least 

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six weeks of age, clinically stable, and are being or have been discharged from the 

hospital nursery. Infants who have recently received any antibody-containing blood 

products may be vaccinated. 

• The small risk of shedding and transmission (after dose 1, by 12%-13%) does not 

outweigh the risk of transmission from a child with wild rotavirus disease to household 

contacts, so the infant should be vaccinated. Vaccine should not be readministered to 

infants who regurgitate a vaccine dose. Limited related safety and efficacy data indicated 

that, since the vaccine has a high titer, even a partial dose might lead to some immune 

response and protection. 

Discussion: 

• Dr. Abramson understood the data-based rationale for the very tight vaccination schedule, 

but strongly advised that very clear guidance be provided on it, as children will certainly 

be presented for vaccination both early and late. Dr. Treanor said that guidance for 

vaccinating outside the window will be developed. 

• Dr. Halsey urged a more permissive recommendation for HIV-positive children. Antiviral 

therapies have greatly reduced maternal transmission of HIV (to only 5%), and 

immunosuppression is minimal until months after birth. Making HIV status a 

contraindication will discourage needed studies from being done. 

• Dr. Poland suggested that the broader definition of altered immunocompetence in the 

General Recommendations be applied, and also edited the “theoretical benefits” phrase to 

be “known benefits outweigh theoretical risks.” 

• Dr. Heaton clarified that the REST design selected the early 6-12 week window because 

the intussusception rate is low at that time, which helped them to ensure that any repeated 

signal of intussusception risk would be detected. Merck has no concern about vaccinating 

at an older age. A first dose at 13 weeks will still be clinically acceptable. The postlicensure studies will look specifically at age issues and at vaccinating HIV-positive 

children. They do not expect the latter to be problematic since this group has received live 

OPV with very few adverse events. 

• Dr. Phil LaRussa, of Columbia University, clarified that most HIV-exposed children will 

have had two negative postnatal tests, one at age ≥2 months, and almost all remain 

negative to 18 months of age. 

• Dr. Deborah Wexler commented on this recommendation’s precaution for moderate to 

severe “febrile” illness, which differs from other recommendations in citing “febrile.” She 

favored consistency unless there is a reason to specify fever. 

• Dr. Heaton said that the clinical trial exclusions may not have been sufficient to prevent 

trial participation by a child with an unrecognized IgA deficiency. And, in terms of shed 

disease, children with natural disease shed ten- or eleven-fold more virus from natural 

infection than they do from a vaccine dose. 

Dr. Allos moved to accept the proposed recommendations, for a universal recommendation 

at 2, 4, 6 months, with the minor changes suggested, and Dr. Stinchfield seconded the motion.. 

Further discussion included agreement that the HIV qualification would be changed from a 

contraindication to a precaution and that the recommendation would say the vaccine “should be 

administered between 6-12 weeks of age.” 

This document has been archived for historical purposes.
Vote

Conflict: Drs. Treanor, Poland 

In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu, Marcuse, Morse, Morita, 

Stinchfield, Womeodu, Abramson

Opposed: None

Abstentions: Treanor, Poland 

The motion passed.

VFC Resolution

Presenter: Dr. Greg Wallace, NIP

With the ACIP’s approved of a general universal recommendation for the rotavirus vaccine, a 

vote was now needed to incorporated the vaccine into the VFC program. This was done in two 

parts; to add the rotavirus vaccine to the VFC’s list of covered vaccines (to now total 15 

vaccines), and then to specify its administration, details of which were lifted directly from the

recommendations: 

• Administer dose one from age 6-12 weeks, with the routine dosage at 2, 4, and 6 months, 

with 4-10 week intervals between each dose, and none given past age 32 weeks. 

• The standard language about referring to the package insert about dosages was included, 

as well as that on serious allergic reactions.

• Language on altered immunocompetence was moved to the Precautions section, 

including that on HIV and other conditions related to immunocompetence. 

• "Febrile" was deleted from the language on moderate to severe illness. 

• Provider judgment was advised for children with pre-existing chronic GI conditions. 

• The intussusception experience of the previous rotavirus vaccine was acknowledged and 

this vaccine was expected to be helpful for children who have had intussusception. 

Studies to date were described. 

Discussion included: 

• Dr. Pickering expressed concern about moving all immunodeficient diseases to the 

Precautions section, since that would include rare primary immune deficiencies (e.g., Tand B-cell deficiencies, x-linked gamma globulinemia) for which this live vaccine should 

not be given. However, Dr. Paul Offit commented that although those children can shed 

virus for long periods, they tend to get mild disease. Even children with severe combined 

immunodeficiency suffer little from natural infection, and he doubted the vaccine would 

be of greater risk. He would delay the vaccine only if the child was about to have 

immunosuppressive therapy such as a bone marrow transplant, and even then the child’s 

age and whether it was rotavirus season would be factors in the decision. 

• Ms. Stinchfield pointed out that HIV had already been moved to the Precautions section, 

not the other primary immune deficiencies. She suggested strengthening the language on 

altered immunocompetence in the Contraindications section to specify “known T- and BThis document has been archived for historical purposes.
cell immunodeficiency,” to protect physicians who may not know by 12 weeks that a 

child has an immunodeficiency. Dr. Abramson agreed. 

• Dr. Halsey addressed the complexity of this question. The AAP has loosened its strictures 

on giving live vaccines to immune deficient infants. They now provide some flexibility 

for vaccinating children with conditions such as B-cell immune deficiency disorders, 

those receiving replacement immunoglobulin, or those with IgA deficiency. There just 

should be consultation with an immunologist or infectious disease person to evaluate 

each situation. 

• Mr. Kevin Malone, of the Office of General Counsel, confirmed that the VFC language 

had to be specific before a vote could be taken. 

• Dr. Sam Katz objected to singling out HIV, as there is no evidence that rotavirus poses an 

undue burden to HIV-positive children. In the U.S., children born to an HIV-positive 

mother will be seen by someone, but that is not the case in Africa, and listing HIV as a 

contraindication to this vaccine will severely affect them.

• Dr. Baylor pointed out that the vaccine label’s precautions include infants with primary 

acquired immunodeficiencies, including HIV/AIDS. 

• Ms. Stinchfield noted that live vaccines such as varicella are given to children with HIV 

who have a normal CD4 count, and questioned why this live vaccine should be treated 

any differently than others. 

• The language advising against administration after 32 weeks would be changed to 

“should be given by 32 weeks.” 

Dr. Pickering regretted that the complexity of the immunology made this decision difficult. Of 

the four major types of deficiency (T-cell, B-cell, phagocytic, and complement), live viral 

vaccines can be given to children with the last two, so grouping all four as contraindications is 

incorrect. But on the other hand, splitting them might make the recommendation too complicated 

for what is trying to be achieved in a small number of children. 

Dr. Wallace agreed to edit the recommendation based on these comments, particularly in the 

Precaution section to advise seeking the advice of a specialist. With that, and language on altered 

dosage intervals, he would return for the ACIP’s vote in the morning. 

ACIP GENERAL RECOMMENDATIONS ON IMMUNIZATION

Revisions to the General Recommendations

Presenter: Dr. Ed Marcuse, General Recommendations Working Group Chair 

Overview: Past and new changes to the ACIP General Recommendations document

The ACIP General Recommendations document is its compendium of the information needed 

about immunization. Its revision every ~5 years is always a challenge, given the rapidity of 

change (or persisting lack of data) in the field. This revision is expected to be released in 

September, pending the ACIP’s approval on this day, perhaps with additional edits. 

General recommendation changes previously presented to the ACIP were:

This document has been archived for historical purposes.
Vaccine administration:

• A 5/8” needle is adequate for intramuscular injection; the reference was removed to the 

7/8” needle, which is no longer produced. 

• There is no need to aspirate prior to vaccine injection 

• There is no preferred site for intramuscular injection, but a cautious preference is 

expressed for the thigh in infants and the deltoid in adolescents and adults. 

Storage and handling of immunobiologics: 

• The language was strengthened to advise keeping vaccine properly stored to the 

expiration date (to stop automatic discard of vials opened >30 days). 

• The recommendation was strengthened to contact the state health department on the 

procedure for mishandled or inappropriately stored vaccines. This is controversial, since 

there are no clear data to guide this decision, and it depends on the vaccine and how it 

was mishandled. Since expert guidance is needed, the Working Group felt the health 

department was the first place to check.

Altered immunocompetence: 

• A permissive recommendation for the use of varicella and pneumococcal conjugate 

vaccine after hematopoietic stem cell transplantation in immunocompromised patients 

was inserted, with a reference.

• A caution was inserted about the use of live vaccines in patients on tumor necrosis factor, 

alpha inhibitors and other isoantibodies, after related advice from experts that these are 

analogous to the effect of high dose steroids. 

Discussion included: 

• Dr. Hull asked rhetorically how a state health department could be expected advise on 

complex issues like vaccine mishandling if the ACIP cannot. He asked if the NIP could 

develop a table or formal guideline to help advise this field. Dr. Kroger reported that the 

revised recommendations will have a table of information for a range of vaccines derived 

from the respected Vaccines by Plotkin and Orenstein. But realistically, most questions 

are case-based, frustrating any kind of standard reply. Contacting the manufacturer could 

be the best suggestion. Dr. Kuter reported that Merck has some algorithms potentially 

helpful to answer the questions of vaccine appropriateness for use. 

• State representatives emphatically agreed that guidance is desperately needed. Dr. Kelly 

Moore, Medical Director of the Tennessee Health Department, developed her state’s 

guidance herself, based on the WHO and Australian guidelines. Ms. Beth Rowe-West, 

who manages the North Carolina state program, reported requests for judgments at every 

site visit. NIP cannot be called for guidance about every refrigerator that is too warm or 

cold, something they hear about “at least twice a day.” 

• There was some opinion that mis-stored vaccine simply should not be administered, to 

protect the integrity of vaccines as a whole. But Dr. Abramson raised the problem posed 

when the mishandling is realized in retrospect. Dr. Moore agreed, reporting common 

experiences of practitioners who found their vaccine frozen and had to contact thousands 

of families thereafter. The final decision is made by an adequately informed parent who 

can require the physician to revaccinate. But, just as fever will not be found without 

This document has been archived for historical purposes.
taking a temperature, such incidents will not be known unless someone looks at the 

temperature logs.

• Dr. Salisbury reported the U.K.’s similar experience. The instances of the 

recommendation being ignored over time, however, are far less than those of a cleaning 

person who forgot to re-plug the refrigerator on Friday evening. Calling the 

manufacturers rarely helps, as they generally just advise consulting the package insert, 

being loathe to risk the liability of any other decision. In his opinion, people just need to 

make sensible judgments; if the vaccine was not out of the cold chain long, it is a 

reasonable risk to use it. It is easier to discard it, but that could be just an expensive 

waste.

• Ms. Lynn Bahta, of Minnesota’s health department, disliked the removal of the previous 

recommendation’s text of what to do if a child receives what turns out to be a nonviable 

vaccine. That removal leaves no national standard at all on which to rely. 

Dr. Abramson recommended that this be discussed further in a conference call. He asked those 

with comments or concerns to email him or Dr. Marcuse about this issue and the changes 

outlined, which will be addressed again in June. 

 

New Revisions to the General Recommendations since October 2005 

Presenter: Dr. Andrew Kroger, NIP 

The entire 2002 General Recommendations document was not revised, but significant new 

changes were made. These have been reviewed by the ACIP liaisons and the Association of 

Immunization Managers. Most of the major changes came from the ACIP statements revised in 

the past four years. These include: 

• Timing/spacing of newly licensed vaccines.

o

o

o

Live vaccines/LAIV: Parenterally administered live vaccines must be deferred 

after receipt of blood products (and vice versa). The deferral period can range 

from 2 weeks to 11 months, depending on which product was given first. This 

interval is necessary because blood products can interfere with replication of 

parenteral live vaccines. . There are no data on this, but subject matter experts’ 

opinion (CDC, Influenza Branch) is that the antibody response to LAIV will not 

be affected by circulating antibody, making unnecessary the interval between 

administration of LAIV and antibody-containing blood products. The new 

language reads: “Yellow fever, oral Ty21a typhoid vaccine, and live attenuated 

influenza vaccine are exceptions to these recommendations.” 

A 28-day interval between LAIV and other live vaccines not given 

simultaneously was recommended by ACIP in 2005. 

The AAP currently recommends a one -month interval between Tdap and MCV4 

not given simultaneously. The new language recommends “No interval between 

LAIV and antibody containing blood products;” a “four week interval between 

nasal or injected live vaccines if non-simultaneous,” and a “1 month interval 

between Tdap and MCV4 if non-simultaneous.” 

• Contraindications and precautions: New vaccines were added to the table: Tdap, TIV, 

LAIV, MCV4, and MPSV, and their contraindications/precautions were taken from the 

This document has been archived for historical purposes.
published vaccine-specific recommendations. There are provisional recommendations for 

Tdap, listing severe allergic reaction and encephalopathy as contraindications. 

Precautions are: moderate or severe acute illness, GBS, progressive neurologic disorder 

until the condition is stabilized, and a history of Arthus reaction, causing severe local 

reactions. For the latter, Tdap vaccination is deferred unless it has been ten years since 

the previous dose. 

• Vaccine administration:

o Tables were added for the new vaccines’ (Tdap, MCV4, MPSV) recommended 

dose and route. This will include the issue of IM-recommended vaccines given 

subcutaneously (e.g., meningococcal conjugate vaccine). A suggestion to include 

combination vaccines will be added, but had not been incorporated when this draft 

was distributed. 

o A table addresses needle length by age (0-10 and ≥11 years), body mass, and site, 

as regards intramuscular injections. Different factors determining appropriate 

needle length for each group are addressed. It calls for the use of at least a 1” 

needle length for all preadolescents, adolescent, and adults. But that also depends 

on body mass; if low, there is a risk of hitting bone. This needs to be addressed in 

more detail.

o A table on the treatment of anaphylaxis addresses only the IM and oral treatment 

regimen, for both pediatric and adult patients. 

• Altered Immunocompetence. A new table presents the recommendations for vaccination 

of persons with altered immunocompetence that were presented to the ACIP in October 

2005. The table is organized by disease categories parallel to those in the AAP’s 2006 

Red Book (i.e., primary-secondary conditions also classified by cell-type, such as B- or 

T-cell deficiencies). The column for "Recommended Vaccines" may be relabeled “RiskSpecific Recommendations By Virtue of Altered Immunocompetence” to avoid the

perception that only the listed vaccines should be used for that specific disease. The last 

column addresses vaccine efficacy and adds comments. 

• Special Situations: 

o LAIV and Protein and Protein-Derivative vaccines reactivity. MMR and varicella 

not administered concurrently to a tuberculin skin test can cause a false negative 

result. The current (2002) recommendation is, when the vaccine is given first, to 

delay the PPD/TST for at least four weeks post-vaccination. For LAIV, a live 

vaccine whose effect on the PPD/TST is unknown, the Influenza Branch subject 

matter experts recommended treating LAIV like other live virus vaccines, spacing 

the PPD/TST four weeks later if it is not simultaneous, or performing the 

PPD/TST first. 

o Severe allergy to vaccine components. The new language clarifies that the 

preservative thimerosal in vaccines given to children has only been in trace 

amounts, or not at all, since mid-2001. It also provides the new recommendations 

for the inactivated influenza vaccine licensed in 2005 for children. 

o Vaccination of internationally-adopted children. In view of the new hepatitis B 

recommendations, the language for international adoptees now recommends both 

a surface antigen test and vaccination as primary approaches. With varicella 

vaccine recommendations, the definition of “immunity” will be taken from the 

varicella-vaccine-specific provisional recommendations. 

This document has been archived for historical purposes.
Dr. Kroger asked for the ACIP’s approval of these revised recommendations subject to the 

inclusion of actions at this meeting and minor revisions of language, format and citations. 

Discussion included:

• Dr. Hull strongly recommended revision to the statement indicating that since mid-2001, 

vaccines routinely recommended for infants and have been manufactured without 

thimerosal. Taken out of context, that sentence has been used to resist state legislation to 

restrict the use of thimerosal in vaccines. He agreed to provide replacement text.

• Dr. Poland reported being asked about the intradermal vaccinia (smallpox) vaccine, and 

recommended including that as well. It was not included because it is not a universally 

recommended vaccine. However, it could be appropriately included to meet the needs of 

such broader use of these recommendations as by the military. 

• Dr. Stan Gall asked about the simultaneous administration, in the postpartum period, for 

RhoGAM, MMR and varicella. Dr. Kroger responded that the 2002 guidance was not 

changed in its direction to give MMR after RhoGAM to protect against rubella. He 

agreed to check the vaccine-specific recommendations on varicella since it is being 

encouraged for postpartum use and, as Dr. Gall noted, there are a fair number of women 

who need RhoGAM at that time. 

• Dr. Jeff Duchin suggested adding to the international adoptee text a recommendation that 

family members ensure they are up to date on their own vaccinations. 

• Dr. Doug Campos-Outcalt, of the AAFP, asked why the hepatitis B surface antigen 

recommendation did not include surface antibody inhibition. Dr. Kroger answered that 

the hepatitis B vaccine-specific recommendations advise use of the surface antigen test 

for large groups of people considered at high risk, in order to identify carriers. The “large 

group” includes international adoptees from high-risk countries, so to simplify matters, it 

was decided to recommend the test for all international adoptees. It was also felt that in 

view of the lack of records, providing the one dose to all also was advisable. Dr. 

Abramson commented that a positive surface antibody test would establish the need for 

vaccination and would be a cost effective way to proceed. Dr. Wexler said that the 

presence of antibody could be maternal in origin, and not vaccine. For that reason, the 

child should receive three doses of vaccine unless they have a document recording those 

doses. But the surface antigen test must be done to identify a carrier. Dr. Kroger added 

that the vaccine might, although rarely, produce a positive surface antigen test. A 

footnote may be inserted to advise serology first, then vaccination. 

• Dr. Schaffner questioned the necessity of the statement about “potential interference 

between LAIV and other live attenuated viral vaccines," since LAIV replicates only in 

the upper airway while the other vaccines are administered parenterally and replicate 

systemically. Dr. Kroger responded that the new language reassures that there is no 

concern about LAIV relative to circulating antibody in blood products, nor about LAIV 

simultaneously administered with another live vaccine. But it does advise the interval 

when LAIV is not administered simultaneously with another live vaccine. But Dr. 

Marcuse raised Dr. Schaffner’s question again, noting that the ACIP to date has not 

considered if there should be any spacing for the LAIV or rotavirus live vaccines. He 

asked if a nonspecific immune response from a parenteral vaccine could prevent a topical 

vaccine’s take, or vice versa. Dr. Plotkin answered that interference could occur for two 

This document has been archived for historical purposes.
reasons: the introduction of interferon, which could be tested, and an effect on cellular 

immune response, primarily CD4. Relevant data from the manufacturers on these 

questions would be good to have. Dr. Jeff Stoddard, of MedImmune, stated that there are 

not yet any data from the ongoing immunogenicity studies to answer that question, but

that would be available soon. In that event, Dr. Marcuse asked if the rule of spacing 

should be continued until more data are in hand. There were nods all around to that 

question, indicating agreement. 

Public Comment

Mr. Gary Stein, of Families Fighting Flu, related that his daughter Jessica had died of influenza. 

People always think that “it can’t happen to us.” That is not true, but individuals can make a 

difference. For those reasons, he attended to encourage ACIP to recommend annual influenza 

vaccination for all children. On the next day, ACIP was to discuss including children aged 2-6 in 

the universal vaccination recommendation. He urged the committee to pass that vote to expand 

this recommendation. It would be a step in right direction, since many pediatricians do not 

recommend influenza vaccination now, and ACIP expansion of the recommendation will spur 

them to do so. He asked that the ACIP act to spare another family the tragedy of losing another 

child. 

Mr. Joe Lastinger, who lost his daughter Emily to influenza, was joined by Richard and Luisa 

Kanowitz and John Bellovich, who also had lost their children to flu. He called ACIP’s 

recommendation critically important. Had it been in place several years ago, Emily might have 

been vaccinated and she would be alive today. He understood the concern about the vaccine 

supply, but he had researched what is available. His impression was, if children to age 6 are 

included, that would add 20 million children to the population for vaccination. CDC’s data 

indicate that 40% of those are already covered due to their health status or that of a household 

contact, so in reality, only ~12 million more children would need to be covered. And of those, it 

is likely that many would not seek the vaccine. Even in his own community, people who knew 

Emily and what had happened to her still do not vaccinate their children. If only 75% do, that 

would be an additional 9 million children. The manufacturers expect to produce 120 million 

doses for the next season. He asked the committee to please consider the millions of children 

who, based on its decision tomorrow, could be vaccinated next year and saved, or not. If the 

members are uncertain, he asked them to please think about these particular children, and the 

hundreds of others who might still be alive today had they been vaccinated. 

With no further comment, the meeting adjourned at 6:03 p.m. and reconvened at 8:00 a.m. on the 

following morning. 

FEBRUARY 22, 2006 

CDC DIRECTOR’S COMMENTS

Presenter: Dr. Julie M. Gerberding, CDC Director

CDC remains committed to the basic public health issues affecting Americans’ daily lives: 

obesity; chronic diseases such as cancer and cardiovascular disease; tobacco use, injuries, and 

This document has been archived for historical purposes.
disabilities. But media attention goes to special issues such as terrorism and pandemics, also 

necessary work, which challenges CDC’s ability to keep its portfolio balanced. 

An outline was provided of the CDC programs funded by its current $8 billion appropriation, 

according to program increases, stable funding and decreases. Funding has increased (1600%) 

since 2001 to build and maintain the Strategic National Stockpile and to respond to terrorism, 

supported the Vaccines for Children program and work on birth defects global immunization and 

environmental health. 

However, the increase for immunization, when adjusted to the price index (an accounting 

method for the cost of science), is actually stable funding. While that is something to be grateful 

for, with increasing numbers of new vaccines and the growth of adult and adolescent vaccination 

programs, strategies realigning resources or reconfiguring programs will be needed to meet 

Congress’ deficit-reduction budget trends. Additionally, the benefit to other programs, such as 

the President's proposed budget’s inclusion of $93 million for domestic HIV/AIDS testing, is 

offset by no funding for the public health work that naturally follows testing, such as partner 

tracing and treatment. 

CDC received $3.1 billion of an emergency $7.1 billion supplemental appropriation for influenza 

pandemic preparedness and response. This will also benefit seasonal influenza response, 

improving seasonal vaccine supply and development of new antiviral drugs; and it has already 

improved CDC’s rapid alert communications capacity. 

These are all part of CDC’s strategy to maximize and extend the benefit from categorical 

investments to much broader applications, by concertedly directing budget resource decisions to 

support very specific health impact goals. Concurrent stressing of efficiencies in-house has 

produced a focused, lean and effective structure that earned CDC the OMB’s commendation for 

appropriate resource utilization. These two approaches are being generalized broadly across 

CDC. Dr. Gerberding thanked the committee, not only for its very hard work to support 

immunization, but also for wise counsel on such resource allocation issues. 

But other programs have lost ground in funding, including occupational safety, injury 

prevention, TB, STDs, public health research, leadership and management initiatives, business 

services support, buildings and facilities, and the youth media campaign. Immunization also still 

faces considerable challenges. More vaccines mean more doses to more people in more age 

groups and communities. This accelerates the increasingly complex process of delivering them to 

those most in need, monitoring and evaluating immunization safety, and scaling up all this to 

match production scale, while maintaining the program’s overall credibility and vaccines’ safety. 

But the challenges fade in the light of such rewarding inaugurations, as addressed at this 

meeting, of another cancer defeated by vaccine (HPV), and the immense impact the rotavirus 

vaccine will have to save children lives worldwide. 

Discussion included: 

• Vaccine distribution. A vaccine summit held recently examined seasonal influenza 

vaccine production and distribution options to close the supply/demand gaps. Production 

This document has been archived for historical purposes.
will rise to at least 100 million doses of seasonal vaccine, and the market will be driven 

to create that demand. The problem with vaccine distribution is that CDC does not own 

the vaccine. Further adjustment with the private sector’s distribution system is needed. 

Last year, it was the smaller purchasers who did not receive vaccine, in part due to 

Chiron’s delayed product release or their own late order. CDC’s VFC purchase also 

commands a lot of the initial supply. One strategy is the join small purchasers into 

groups to gain more clout. Another is production modernization, but that may take 3-5 

years.

• Vaccine financing systems. Multiple and perhaps combined solutions will be needed to 

address the many components of vaccine financing. Only one aspect is risk versus profit 

(e.g., the egg-based influenza vaccine process, and Viagra versus other therapeutic 

vaccines). Government purchases also help to ensure a reliable market.

• Dr. Abramson noted ACIP’s mandate to examine the safety/efficacy and cost 

effectiveness of vaccine, but not the funding implications. There is concern about the 

possibility substantial social inequity that could result from unequal access to the new 

vaccines. Dr. Gerberding acknowledged that many public health investments, as a matter 

of policy, have to balance the potential benefits. She hoped to hear more of these 

concerns and potential resolutions. Dr. Gellin reported that the National Vaccine 

Advisory Committee (NVAC) has begun to address those issues, which differ from the 

ACIP’s mandate, and they also increase focus on vaccine financing. 

• CDC reorganization. Dr. Schuchat reported that the Coordinating Center for Infectious 

Diseases holds three CDC infectious disease centers: the NIP, NCID and NCHSTP. But 

over the next month, the NIP will transition into a larger activity tentatively being called 

the National Center for Immunization and Respiratory Diseases, to link vaccine-related 

work from the laboratory bench through vaccine delivery and immunization services, 

including influenza activities. 

OLD BUSINESS

Resolution to Add Rotavirus Vaccine to the VFC 

Presenter: Dr. Greg Wallace, NIP

Dr. Wallace presented the revised resolution, which incorporated the edits from the previous day. 

It specified that dose one should be initiated for infants aged 6-12 weeks and notes that the last 

dose should be administered by 32 weeks of age. 

Two options were offered to address altered immune status, which was formerly a 

contraindication to vaccination. This could be moved this to the Precautions section, advising the 

physician to consider the potential risks and benefits for infants with, for example, lymphoma 

and other immunocompromised conditions. And, severe immunodeficiency such as severe 

antibody deficiency or severe combined immunodeficiency could be cited under 

Contraindications. 

Discussion included the implications to Medicaid payment if a child aged >32 weeks receives a 

third rotavirus dose at an office visit. The committee was reminded that the VFC not a 

reimbursement program; it only provides vaccine to VFC providers. The members were advised 

This document has been archived for historical purposes.
to simply recommend on the technical issues. The resolution clearly states that if eligible, the 

child should receive the vaccine. Any impact on VFC program would have to be addressed by 

the Office of General Counsel. The VFC auditors will note vaccine administered outside of the

recommended time frame, but are unlikely to penalize the practice. Dr. Marcuse asked if the 

footnote on this could simply be removed from the resolution. But Dr. Seward recommended 

retaining the age recommendation, given the removal of the “should not be” wording, 

reassurance that VFC children will be covered at >32 weeks, and that the new wording is 

consistent with the package insert and ACIP recommendations (which will be revised). Ms. Lynn 

Bahta agreed, adding that the footnote is instructive to the practitioner.

Dr. Marcuse moved to accept resolution as presented, but to remove the footnote on the 

dosing interval. Dr. Morse seconded the motion. 

Vote

In favor: Marcuse, Poland

Opposed: Beck, Campbell, Finger, Gilsdorf, Lieu, Morita, Treanor, Womedou, Abramson

The motion failed. 

Dr. Finger moved to accept the resolution as presented with grammatical corrections. Ms. 

Stinchfield seconded the motion. 

Vote

In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu, Marcuse, Morita, Poland, 

Stinchfield, Treanor, Womedou, Abramson 

Opposed: None 

Abstained: None. 

The motion passed.

Additional comment. Dr. Mark Feinberg, of Merck, requested an edit for clarification and 

completeness. Rather than, as now stated, referring to the vaccine’s safety when administered 

after 12 weeks of age, as based on data from the clinical trial, he suggested text to say "safety or 

efficacy of the vaccine administered, the first dose administered after 12 weeks of age." 

However, since this was suggested after the vote, it was not incorporated into the VFC 

resolution. 

Vaccine Storage. Dr. Abramson reported a decision by NIP to meet with the Association for 

Immunization Managers to discuss possible solutions to the issue of improperly stored vaccine, 

to help refinement of the ACIP wording. They will discuss what additional information might be 

available (e.g., from the Australian guidelines or the manufacturers), and potentially needed 

educational initiatives and research. 

Changes to the ACIP General Recommendation 

This document has been archived for historical purposes.
Presenter: Dr. Andrew Kroger, NIP

Needle length. The wording was revised as suggested on the previous day. The Working Group

will continue to discuss table revisions for intramuscular (IM) injection based on age, body mass, 

and site, to provide all the data sources. The ACIP accepted this as presented.

Severe allergy to a vaccine component (i.e., influenza vaccine/thimerosal). With inactivated 

influenza now the standard recommendation for children, new language was needed: 

"Since 2001, inactivated influenza vaccine is the only vaccine routinely recommended for 

children under two years of age that contains thimerosal as a preservative. Inactivated influenza 

vaccine also may contain trace amounts of thimerosal that are residual from the manufacturing 

process. A thimerosal-free formulation of inactivated influenza vaccine for use in children was 

licensed in 2005. TT, Td, and DT vaccines contain thimerosal as a preservative.” 

Matters remaining to be discussed were the necessity of a spacing interval with nonsimultaneous administration of LAIV and other live vaccines, and RhoGAM immune globulin 

and varicella; the issues (including cost effectiveness) related to repeated vaccination for 

international adoptees with unknown hepatitis status, including the conduct of a hepatitis B 

surface antigen test and a hepatitis B surface antibody test. Language will be added to address 

vaccination of family members of international adoptees. 

Discussion included: 

• Dr. Hull suggested just having the table say that vaccines may contain preservatives to 

maintain their potency and safety, then listing those that might have preservative. There 

was general agreement to that recommendation

• Mr. Phil Hosbach, of SanofiPasteur, reported that Tt and Td also are available with only 

trace amounts of thimerosal.

• Dr. Baylor asked that the FDA Website be referenced, which will also be useful with new 

vaccines released in future. 

Altered Immunocompetence 

Dr. Katz asked a question in reference to the changes needed to Table 11, specifically relabeling 

of “Recommended Vaccines” column to clarify the vaccines recommended for people with 

altered immunocompetence. Dr. Abramson clarified, on Dr. Katz’ question, that Table 11 would 

be modified. There may be other edits, but neither Table 11’s nor any others were expected to be 

substantive. 

Ms. Stinchfield moved to approve the ACIP General Recommendations with the 

modifications presented. Dr. Poland seconded the motion 

Vote

In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu, Marcuse, Morita, Poland, 

Stinchfield, Treanor, Womedou, Abramson 

Opposed: None 

Abstained: None. 

This document has been archived for historical purposes.
The motion passed unanimously.

VARICELLA ZOSTER IMMUNE GLOBULIN

VZIG Update: Availability of a New Product

Presenter: Dr. Mona Marin, NIP 

In 2004, the only U.S.-licensed manufacturer of varicella zoster immune globulin (VZIG) 

announced their withdrawal from the market. CDC’s literature search on possible VZIG 

alternatives was presented to the Varicella Working Group and, in October 2004, ACIP 

recommended the use of intravenous immune globulin (IGIV). However, VZIG was preferred 

for post-exposure prophylaxis of patients at high risk of complications and severe disease. The 

VZIG supply was expected to last to April, 2006, but will probably be exhausted by March 1. 

By July 2005, CDC, FDA and subject matter experts decided that, in view of weak scientific data 

supporting an alternative method, FDA should encourage new IND applications for immune 

globulin. Given the impending depletion of VZIG supply, FDA made an IND, Varizig®, 

available in February under an expanded access protocol. Varizig® is manufactured by Cangene 

Corporation, Canada. It is a lyophilized, purified human immune globulin preparation made from 

plasma, with high levels of antivaricella antibodies, immune globulin Class G. When 

reconstituted, is provides a ~5% IgG solution for IM administration. As an IND, administration 

requires informed consent. 

The Varizig® indication is for patients exposed to varicella, who have no immunity from natural 

disease or age-appropriate vaccination, and who are at high risk for severe disease and 

complications. These are the same patient groups who would receive VZIG: those who are 

immunocompromised; pregnant women; neonates whose mothers developed varicella symptoms 

from <5 days before delivery to two days after; premature infants of >20 weeks gestation who 

are exposed as neonates and who have varicella naïve mothers; and those <28 weeks' gestation or 

who weigh ≤1,000 grams at birth and who are exposed as neonates, regardless of maternal 

varicella history. 

Providers should make every effort to obtain and administer Varizig® to these groups as soon as 

possible after exposure, and it can be administered as late as 96 hours; it. When that cannot be 

done, one dose of IGIV can be used as an alternative, at a recommended dose of 400 mg/kg. That 

is also true for pregnant women, or the physician may choose to closely monitor her for varicella 

symptoms and begin acyclovir treatment if illness develops. The vaccine comes in 125-unit vials. 

The recommended dose is 125 units per 10 kilograms of body weight up to a maximum of 625 

units (five vials); the minimum dose is half a vial, 62.5 units for patients weighing <5 kilograms. 

Standard varicella vaccination should follow Varizig® in the absence of any contraindications, 

but only after an interval of five months after Varizig®. The vaccine is unnecessary if the 

patient develops varicella after receiving Varizig.®

FFF Enterprises distributes Varizig® under the expanded access protocol. It has received central 

IRB approval; local IRB approval is not required, but they should be informed of the protocol. If 

This document has been archived for historical purposes.
they reject the central IRB’s jurisdiction, the Varizig® can still be shipped but the local IRB 

must supervise its administration. In an emergency, Varizig® can be used once without regard to 

IRB review requirements, to ensure the patient is promptly treated. But that must be reported to 

the IRB within five working days and the IRB must review any subsequent Varizig® treatment. 

Interested pharmacies and healthcare providers can fill out the FFF forms in advance to be 

prequalified to receive and use Varizig®. When needed, the completed release can be faxed to 

FFF, which determines patient eligibility and assigns a patient number to those eligible. Or, FFF 

can provided the product release form upon request to its 800 number, fax or e-mail it back and 

begin the process. Generally, Varizig® can be provided within 24 hours. This information will 

be published in the MMWR.

Discussion included a report that, aside from the MMWR notice, Varizig’s® availability will be 

published in medical journals, and promoted at the conferences held nationwide by the 

Department of Education and Communication. Details can also be received from FFF. The 

MMWR will also be circulated to professional associations and the ACIP liaisons, and the ACIP 

members also were encouraged to promote it within their own fields. There is a link to FFF’s 

standard two-page request form on the FDA Website as well. This presentation’s slides and all 

others presented at this meeting were to be posted on CDC’s Website within a week. 

INFLUENZA VACCINE

Introduction

Presenter: Dr. Ban Allos, Influenza Working Group Chair 

The Influenza Working Group has met monthly, and on occasion bimonthly, to discuss vaccine 

composition changes for the 2006-2007 season; to develop a recommendation on the use of 

adamantanes (as >90% of the strains are resistant to them this season); to develop a suggested 

ACIP recommendation related to vaccine tiering, and to suggest an ACIP encouragement to 

vaccinate children aged 24-59 months this year, that would be expanded to an recommendation 

the following year. 

The working group also discussed the rationale for extending influenza vaccination 

recommendations to persons at risk for nonhuman influenza (e.g., those working with animals, 

poultry, or swine and travelers to areas affected by avian flu) as a way to prevent reassortment; 

this plan was ultimately not adopted by the group. Finally, a universal influenza vaccination 

policy may eventually be recommended after the working group reviews the existing data and 

data gaps. 

To date, the vaccine’s safety, ability to prevent hospitalizations and deaths, feasibility, and 

economic aspects have influenced expansion recommendations. The working group 

acknowledged that the proposed expansion of recommendations for influenza vaccination to 

include children aged 24 through 59 months of age represented a paradigm shift -- one based on 

prevention of outpatient, ED and pediatrician visits. Future changes to the recommendations 

may consider the indirect effects of vaccination and prevention of the theoretical risk of 

reassortment. 

This document has been archived for historical purposes.
Review of 2005 Influenza Vaccine Summit Meeting.

Presenter: Dr. L.J. Tan, AMA 

Overview: Activities and recommendations of the 2005 Influenza Vaccine Summit 

Dr. Tan outlined the content of the Influenza Summit referenced by Dr. Gerberding, which was 

held January 24-25. The Summit’s presentations and complete minutes are on the Web site 

www.ama-assn.org/go/influenzasummit. These summits have been cosponsored by AMA and 

CDC since 2001 to address influenza vaccine supply issues. 

The January meeting involved 112 organizational stakeholders in the pubic/private partnerships 

related to influenza vaccination (e.g., manufacturers, distributors, professional medical 

association, pharmacists, health insurance, etc.) Its objectives were to identify vaccine supply, 

ordering, and distribution issues in the last influenza season; to review any trends revealed by 

survey data; to develop recommendations on those issues; and, to develop subsequent activities. 

Among the issues identified were: 

• Vaccine supply and distribution. Summit recommendations included: ensure timely 

information regarding vaccine distribution and supply that is effectively communicated 

to providers, public, and the media, by all stakeholders in influenza immunization; ensure 

a transparent vaccine-distribution system that is seen as equitable, with clear, timely, and 

frequent communication to providers about vaccine ordering and shipment policies; and 

encourage optimal vaccine usage to avoid vaccine disposal at season’s end (e.g., noreturn policies; government purchase; tax credits for returned vaccine). The many 

partners of the Summit supported preseason stockpiles for CDC from multiple 

manufacturing sources to buffer the effect of a manufacturer’s production failure 

• CDC tiering recommendations. The summit wrote a letter to ACIP noting that while the 

recommendations are national, vaccine supply issues are regional, due to regional 

implementation. The Summit recommends that tiering should only be used when there 

are issues of vaccine supply and if implemented, a standard but flexible plan should be 

created for such implementation. Tiering implementation must be consistent across all 

providers and its removal should depend on regional-level vaccine supplies. 

• The vaccine testing and release process needs to be as efficient as possible to help resolve 

long-term vaccine supply. 

• Recommendations to reinvigorate demand included moving toward universal 

immunization and encouraging research on related data gaps (e.g., research relevant to 

school-age children aged 6-19). This issue is considered by the Summit as critical to 

long term stability of influenza vaccine supplies and to reaching the Healthy People 2010 

immunization-related goals. 

• The impact of vaccine shortages on the performance measurement of institutions (e.g., 

hospitals, long-term care facilities) has to be acknowledged. If vaccine is unavailable, 

institutions should not be held to those performance standards. 

• Influenza vaccine tracing is needed at all levels, as is a clear definition of the related 

federal, state, and local government roles in obtaining and distributing vaccine. 

Legislation to ban thimerosal-containing influenza vaccines and all thimerosalcontaining vaccines is being advanced to the state level and the Summit urges that 

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partners become involved in legislator education on the science of the issue.

• Improve vaccine demand, especially for the predicted >100 million doses anticipated for 

the 2006-2007 season. Educate and target high priority populations better; target 

education on vaccine’s cost effectiveness to third-party payers and employers; extend the 

immunization season; plan for when there is excess vaccine; and, as discussed on the 

previous day by Families Fighting Flu, give influenza disease a “face.” 

• The manufacturers should limit partial shipments, especially if there is no shortage. Any 

partial-shipment policy should be consistent and well communicated to providers. Prebooking and distribution data for influenza vaccine should be available at least to public 

health. The providers without vaccine should be identified at the beginning of the season, 

to ensure that they get vaccine if there are any supply gaps. 

• Vaccinate healthcare workers. 

Summit accomplishments included: 

• Establishment of a vaccine-supply task force to address supply and distribution 

challenges; the letter to ACIP discussing the inadequacy of the tiering system; expressing 

support for universal influenza immunization recommendations; and, urging ACIP to 

promote vaccine use in a timely and clear manner. 

• The Summit Communications Working Group and its Executive Committee have begun 

examining short-, mid-, and long-term vaccine communication needs. A Reimbursement 

Working Group is analyzing influenza vaccine coverage from the perspective of thirdparty payers.

• A statement will be issued on the importance of establishing a national adult 

immunization program.

• The summit is working with CDC, manufacturers, distributors, and partners to identify 

the data available to better track vaccine and determine how it could be accessed. 

• FDA and the manufacturers are being urged to study how vaccine production can be 

optimized.

The summit is interested in leading development of a partnership to develop a national, 

coordinated strategy for seasonal influenza, in terms of influenza prevention as well as vaccine 

production and utilization, to lower its overall morbidity and mortality. 

Presentation by National Foundation for Infectious Diseases 

Presenter: Dr. Carol Baker, President-Elect

Overview: NFID position on influenza burden on and vaccination need by children 

with asthma.

Despite years of recommendations to vaccinate children with asthma for influenza yearly, it 

appears that rates are low (<40%) given that these children are not routinely assessed for the 

need for vaccination against influenza. Two studies, in a large HMO and an asthma clinic, 

examined influenza vaccination in children. The former had 10% coverage; the latter, 25%. 

In response, the NFID convened a roundtable in November of 2005 with representatives of ~20 

major medical and public health groups. After a full day’s discussion of the known data about 

This document has been archived for historical purposes.
influenza and its impact on children with asthma, they arrived at several key messages, which 

were published in a Call to Action that was available at this meeting. Its key messages are:

• Influenza and other respiratory viruses can be deadly for children with asthma. Viral 

respiratory infections precipitate wheezing in asthmatic children. Influenza is the only 

vaccine preventable viral respiratory infection. Morbidity is increased in asthmatic 

children with influenza; they receive more antibiotics and are much more likely to have 

an outpatient medical visit.

• Asthma puts millions of children at increased risk of morbidity and mortality. Over 6 

million American children have asthma and it is an urban epidemic. It is the third leading 

cause of children’s hospitalization and precipitates ~750,000 ED visits by in children 

aged <15 years. In 2002, 170 children <15 years died of asthma-related causes. In the 

2003-2004 influenza epidemic, 45% of the 153 children and adolescents who died from 

influenza had asthma. 

The NFID call for action invites a comprehensive effort to: 1) increase influenza vaccination 

rates, especially for asthmatic children; 2) add or increase the annual influenza vaccine outreach 

activities to asthma education programs and treatment guidelines; 3) support practice-based 

efforts; 4) increase local influenza vaccination rates, and 5) use public health forums to advertise 

influenza as a vaccine-preventable disease, and the need of children with asthma for the 

vaccine’s protection. ACIP’s help in this initiative, by strengthening its own recommendations, 

will be appreciated by the NFID.

Update on Influenza Antiviral Resistance 

Presenter: Dr. Alexander Klimov, NCID 

Overview: Recent antiviral resistance and WHO/FDA-recommended influenza vaccine 

composition for the next season 

Adamantanes resistance. Resistance to adamantanes (amantadine and rimantadine) can emerge 

rapidly as a result of a single mutation in the influenza virus’ M2 protein. Over 7,000 human 

influenza A (H3N2) viruses isolated worldwide were tested at CDC in 2005. An alarming 

increase in the proportion of viruses resistant to adamantanes was observed in several Asian 

countries. In previous seasons, the proportion of resistant A/H3 viruses circulating in the U.S.

has increased from ~1% (1994-2004) to 12% in 2005. 

Recently, more than 200 Type A isolates collected in the U.S. from October through December 

2005 were tested at the Influenza Branch, CDC. Most of the tested viruses were of the H3N2 

subtype and few were of H1N1 subtype. Of the influenza A(H3N2) isolates, 92.3% had the Ser31-Asn amino acid change in the M2 protein and were amantadanes-resistant. The proportion of 

resistance among few H1N1 isolates was found to be 25%. 

CDC published a health alert on January 14, 2006, and recommended against the use of 

amantadine and rimantadine for the treatment or prophylaxis of influenza in the U.S. during the 

2005-06 influenza season. The data about resistance of currently circulating viruses to 

adamantanes were published in the MMWR (dispatch) on January 17, 2006 (vol 55, pp. 1-2) and 

in JAMA on February 1, 2006 (JAMA, 2006;295:891-894). 

This document has been archived for historical purposes.
Vaccine composition for next season. Data collected by WHO collaborating center laboratories 

(including one at the Influenza Branch) were charted. Influenza A (H1N1) comprised 19% of 

the circulating strains, mostly in Asia and Africa. Influenza A (H3N2) isolates comprised 45% 

of the strains, predominating in North America, followed by Asia, Africa and Europe. 

B/Victoria-like viruses held 27% of the share, with Africa leading, followed by fairly even rates 

in Europe and North America and some in Asia. B/Yamagata-lineage viruses were the least seen 

strains (9%). So, the most common (64%) strains circulating were of type A, with H3 

dominating, followed by influenza B viruses. 

A new antigenic variation of H3 was identified. Also, B/Victoria-lineage viruses became 

predominant (75%) over B/Yamagata-lineage isolates (25%). 

In response, WHO announced on February 15 that the H1 vaccine component would be the 

same: A/New Caledonia/20/99(H1N1)-like virus. The H3 vaccine component was replaced by 

A/Wisconsin/67/2005 (H3N2)-like viruses (recommended strains for vaccine production are 

A/Wisconsin/67/2005 and A/Hiroshoma/52/2005). B/Victoria-lineage strains, 

B/Malaysia/2506/2004 and a B/Malaysia-like virus – B/Ohio/1/2005 – were recommended as the 

type B component of the vaccine. FDA’s Vaccines and Related Biological Product Advisory 

Committee (VRBPAC) agreed with the WHO recommendations. 

Influenza Surveillance Data Update 

Presenter: Dr. Katherine A. Poehling, Vanderbilt University 

Overview: Inpatient and outpatient surveillance data from the New Vaccine Surveillance 

Network (NVSN) (2001-2004) and published data. 

CDC’s NVSN is a population-based, laboratory-confirmed influenza surveillance network in the 

counties of Rochester, New York; Cincinnati, Ohio; and Nashville, Tennessee. The influenza 

burden among children aged ≤5 years was surveyed among in-patients in three counties over four 

influenza seasons, who were admitted for ARI or fever. Out-patient surveillance was done in the 

same three counties from 2002-2004. This was done in the only pediatric ED in the three 

counties, and in 1-3 outpatient clinics per county. Cases for both groups were confirmed by PCR 

or viral cultures. 

A preliminary sub-analysis was done of NHIS parental reports nationally, indicating that 5% of 

children aged 6-23 months are at high risk, as are ~10% of children aged >2 years. For both, the 

primary high-risk condition is asthma, which is diagnosed twice as much in children aged >2 

years than in the younger children (10.6% versus 5.2%, respectively). The mean rates of labconfirmed influenza-related hospitalizations were calculated per 1000 healthy children and then 

for low- and high-risk children, for three age groups: 0-5 months, 6-23 months, and 2-5 years of 

age. The results were as follow. 

Hospitalization rates are high in children aged 0-23 months, at 4.5/1000, versus 0.9 for 6-23 

months (0.65 for low-risk and 5.38 for high-risk) and 0.3 for age 2-5 years (0.25 and 0.75 for 

This document has been archived for historical purposes.
low- and high risk, respectively). Conclusion: Those data support the current recommendation 

and, since these rates decrease with age, a universal recommendation may not be supported. 

Outpatients. For the 13-week influenza season, outpatient (clinic and ED) visit rates were 

calculated using data from the NVSN and the National Ambulatory Medical Care Survey 

(NAMCS) and the National Hospital Medical Care Survey (NHMCS) survey. The rates were 

similar in the mild 2002-2003 season. But in 2003-2004, the rates were about three times higher 

for the high-risk group, although comparable between all children and those at low risk. The 

published Tennessee data of 19 influenza seasons (Neuzil et al, NEJM 2000) showed and 

average of ~90-100 outpatient visits per 1000 children aged 2-4 years, and ~80/1000 among 

those aged 5-9 years. For those children aged ≥2 years, ~80% were prescribed antibiotics. 

Conclusion. The outpatient data indicate rates potentially sufficient to encourage or recommend

vaccination of healthy children aged 24-59 months. Other than direct effects, the expanded 

vaccination may produce herd effects. Influenza surveillance should include older children and 

adults to monitor related policy effects. 

Discussion included: 

• This preliminary analysis could not explain why a smaller effect emerged from high risk 

conditions among both out- and in-patient visits by children aged 2-5 years. It could be 

that the higher vaccination rates being seen include those higher-risk children. 

• The two B lineages are of different genetic and antigenic groups; human serology data on 

the anti-hemagglutination antibody level of the Yamagata lineage indicate a >50% 

difference to B Victoria. 

• Dr. George Peter suggested, as this type of analysis moves to older-age groups of 

children, to consider using the potentially sensitive marker of school absenteeism for 

earlier outbreak detection.

• Dr. Nichol complimented Dr. Poehlingh on the data for children age <5. She hoped ACIP 

would fully recommend vaccination for that age group in spring or summer, especially if 

abundant doses are available. She also supported Dr. Baker’s suggestion to improve 

attention to children at higher risk. That could be accomplished by enhanced ACIP 

recommendation language, and/or publication of a Notice to Readers in the MMWR. She 

added that high risk adults aged <65, whose immunization rates also are low, might be 

added. 

• Dr. Lieu agreed and reported a similar cost analysis being done by her and Dr. Lisa 

Prosser to advance vaccination of children aged 2-18 years. These data will well 

supplement that work, which suggests that universal vaccination would be very cost 

effective and good policy. 

• Dr. Tan reported that an AMA task force is examining supply and distribution issues for 

short-term contingencies and to reach the long-term goal of increasing demand. From 

both that analytical perspective and philosophically, the AMA supports universal 

immunization recommendations.

• Dr. Temte reported analysis of Wisconsin’s sentinel surveillance data, indicating 

surprisingly high percentages of children age 0-4 years presenting to clinics for ILI. They 

do not progress to hospitals or EDs, but are conveying influenza to all their contacts. 

Key Issues/Changes Proposed for the 2006-07 Influenza Recommendations 

This document has been archived for historical purposes.
Presenter: Dr. Nicole Smith, CDC Influenza Branch 

The changes proposed for the next season’s influenza recommendations were to: 

• Change the vaccine composition as described, to two new strains for the influenza A 

(H3N2) virus and influenza B vaccine components. The influenza A (H1N1) virus 

component remains unchanged. 

• Recommend against the use of adamantanes this season.

• Change wording on vaccine tiering to advise against prioritizing without a vaccine supply 

delay or decrease, and to prepare for contingencies if a disruption to the vaccine supply 

occurs. 

• Recommend vaccination to prevent illness among an expanded group of young children, 

encouraging vaccination of children aged 24 through 59 months of age. The Influenza 

working group will present data in October regarding whether other age groups should be 

considered for inclusion among the groups for whom annual influenza vaccination is 

recommended.

• Additional edits to these recommendations reiterate the importance of two doses for 

children not vaccinated previously, and emphasize that influenza vaccine should be 

offered throughout the season. Other updates on the influenza vaccine products, 

coverage level changes, and references will be included in the revised statement. 

Options presented to ACIP for the influenza-related recommendations, with pros and cons, were: 

1. Continue the current recommendation to annually vaccinate children 24 through59 

months of age with high risk conditions, or if the children are household contacts of high 

risk persons. Change the wording on tiering and recommend against the use of 

adamantanes, and the additional edits. Advantages: This option is potentially the most 

feasible; it allows for a continued focus on efforts to improve the vaccination coverage 

levels of existing priority groups and it provides an opportunity to see if the vaccine 

supply is stabilized. Disadvantages: This option continues the risk-based 

recommendations for children aged >24 months, and it does not take advantage of 

expected increased vaccine supply, which could be used to help vaccinate more people, 

including children 24 through 59 months of age. 

2. Option 1, plus encourage annual vaccination of children aged 24 through 59 months 

beginning in 2006-2007; defer the full recommendation until the Working Group presents 

their analysis in October about the potential inclusion of other ages in the 

recommendation. Advantages: This option incorporates a broader understanding of the 

true burden of illness; it may help to reduce the risk of influenza-related complications 

for all children aged 24 through 59 months (not just among those children who have high 

risk conditions); and it gives the vaccine manufactures advance notice of the potential 

need for increased vaccine production in 2007-08, while not producing a huge immediate 

increase in vaccine demand. Disadvantages: The use of encouragement language 

presents a less-clear recommendation that may confuse parents, providers, and payers; 

the evidence in support of routine vaccination is not as strong as for other high risk 

groups; this approach sets a precedent of using ambulatory care visits as a measurement 

of burden of disease; and, if there are vaccine supply delays or interruptions, this option 

could strain the vaccine supply available to reach young children. 

This document has been archived for historical purposes.
3. Option 1, plus recommend annual vaccination of children aged 24 through59 months of 

age beginning in 2007-2008. Advantages: The same advantages as Option 2, except that 

a recommendation is more likely to be implemented and therefore a greater reduction in 

the risk of influenza-related complications for all children 24 through59 months of age 

might be expected. Disadvantages: Same as Option 2. 

4. Option 2, plus encourage routine vaccination of household contacts and out-of-home 

caregivers of children aged 24 through 59 months beginning in 2006-2007. Advantages:

This option should raise the awareness of the importance of influenza vaccination and the 

concept of protecting others; it is consistent with other recommendations for vaccinating 

household contacts and caregivers; it takes advantage of the expected increase in vaccine 

supply to reach household contacts and caregivers; and it may increase the public’s 

demand for influenza vaccine, thereby offering manufacturers an incentive to increase 

their production of influenza vaccine. Disadvantages: Same as Option 2. 

Discussion: 

• Mr. Phil Hosbach reported sanofi pasteur’s plan to make 50 million doses of influenza 

vaccine which should be enough to cover the extra children covered. Sanofi’s 

production also could be increased by 1-2 million doses if necessary. 

• In response to a question by Dr. Joseph Bresee, of the Influenza Branch, all of the ACIP 

members indicated that they agreed with the language on amantadanes and tiering 

changes. 

• Dr. Gilsdorf asked if 50 million doses would be enough. Dr. Smith reported that National 

Immunization Survey data from the first two years of the recommendation encouraging 

influenza vaccination. The proportion of children 6 through 23 months of age who were 

reported as being fully vaccinated against influenza increased from 4.4% in 2002-03 to 

only 8% in 2003-04, but children in this age group who received one or more doses of 

influenza vaccine increased from 7.2% to 17.5%, respectively. National Immunization 

Program staff have developed preliminary estimates indicating that an additional 5.3 

million healthy, 24-59 month-old children who are not household contacts of high risk 

persons would be covered by the proposed change. Behavioral Risk Factor Surveillance 

System data indicate that ~39% of these children would have been previously vaccinated, 

and, therefore would only require one dose of influenza vaccine per year (compared to 

two doses for previously unvaccinated children in this age group). 

• There was an inquiry regarding whether vaccinating older children could reduce the 

disease burden in the 0-6 month-old group through herd immunity; Dr. Smith was unsure 

of the data and noted that the working group was planning to present a review of the data 

at the October ACIP meeting. In the meantime, Dr. Smith highlighted that the ACIP was 

currently being asked to consider the direct benefits of reducing the risk of influenzarelated emergency department and outpatient visits among children 24 through 59 

months of age.

• Although no formal Vaccines for Children Program (VFC) resolution could be voted 

upon until there is a full ACIP recommendation, a permissive VFC resolution would 

allow the use of influenza vaccine for any VFC eligible child, regardless of his/her age. 

Dr. Wallace reminded the committee of the complexities of the influenza vaccines’ 

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different formulations. SanofiPasteur produces a pediatric formulation of the influenza 

vaccine that is approved for use among children 6 through 35 months of age. During the 

last two years, sanofi has not distributed all of its doses of this product. The vaccine 

produced by sanofi for children 3 years of age and older is also used by adults and, 

therefore, there is competition among the different age groups for that presentation. The 

Chiron-produced influenza vaccine can be used for children 4 years and older, but they 

have had some production issues during the last two years. FluMist, the live attenuated 

influenza vaccine produced by MedImmune can be used for healthy children 5 years and 

older. 

• Andrew McNight, of GlaxoSmithKline, reported their plan to produce 20-30 million 

doses of influenza vaccine for the American market this next season (2006-07). The 

vaccine will be licensed for persons ages >18 years in the U.S., but is licensed abroad for 

use in persons ≥6 years of age. Eventually, GSK expects to produce influenza vaccine for 

the U.S. that will be approved for younger age groups. 

• Dr. Poland confessed to being bothered by “creeping incrementalism.” Bicycle helmets 

are recommended, knowing there are not enough, as are annual mammograms without 

enough facilities to do them. Already, 40,000 people die annually of a vaccinepreventable disease. And, with the development of resistance to adamantanes, use of 

antivirals for treatment of influenza is less of an option. Health care workers are 

frustrated with the additional groups added every year and the “ticking clock” of 

pandemic influenza threatens co-infection and reassortment. Dr. Poland declared that 

now is the time for ACIP to be bold and to recommend influenza vaccination for all 

Americans; the recommendations could be phased in over time. No other strategy would 

so well galvanize all involved, from the manufacturers to governments. It would point 

out the high risk target groups while also clearly articulating the vaccine’s rationale at the 

community and population levels. He suggested a universal recommendation could be 

phrased as follows: “Annual influenza vaccination is encouraged for all Americans to 

reduce morbidity and mortality, work and school place disruption, and infection. It also 

aids pandemic preparedness, phased in over time. There also are specific age and 

condition recommendations for groups who should receive priority for vaccine.” 

• Dr. Ben Schwartz, of the National Vaccine Program Office, reported on the October 2005 

meeting on readiness for a universal influenza vaccination recommendation. The 

attendees agreed t hat there is a large burden of illness associated with influenza and that 

the overall effectiveness of influenza vaccine is not optimal and varies by season 

depending upon the circulating strains and vaccine match. Workshop participants 

acknowledged information gaps remain on the indirect effects of vaccinating some 

populations (e.g., incomplete data on the benefit of school children to reduce disease 

among family members and the elderly), and on the effectiveness and safety of repeated 

annual vaccinations. For example, some data indicate decreasing effectiveness among 

some children with cystic fibrosis. The cost effectiveness of influenza vaccination 

depends on several factors, including vaccine cost and the population being targeted, and 

feasibility was raised by immunization managers. Ultimately, the meeting participants 

reached consensus to move toward a universal recommendation, but recommended that 

implementation occur in stages over time to avoid unintended consequences and to have 

time to fill the information gaps. 

This document has been archived for historical purposes.
• Dr. Jacques Morena, of the Immunization Safety Office, urged that if ACIP were to 

recommended more studies and data to support a universal recommendation, it should 

also recommend the funding to do so. 

• Dr. Baker strongly recommended extending the recommended age group fro vaccination 

to 59 months of age (Option 3) and urged ACIP to skip encouragement language in favor 

of a direct recommendation. She argued that the option would ensure that influenza 

vaccination for children 24 through 59 months of age would be covered by private health 

plans and VFC, that pediatricians would adopt the practice, and that currently 

unvaccinated asthmatic children would be vaccinated along with children. Dr. Neuzil 

agreed with Dr. Poland, with a feasible incremental approach. If monitored with the New 

Vaccine Surveillance Network, the public health infrastructure also could be established 

so that eventually, the effectiveness of the influenza vaccination recommendations for 

older children and adults could be evaluated. 

• Dr. Jim Turner, of the American College Health Association, also agreed with Dr. 

Poland’s proposal, which Dr. Turner had recommended 4-5 years ago. He offered 

another variation on the proposal: rather than saying “persons at high risk of 

complications should consider getting the vaccine,” just saying “persons should 

consider...” 

• Dr. Walter Orenstein opposed using the word “encourage,” because it does not help 

clinicians dealing with private insurers nor does it set a clear standard of care. He 

advised ACIP to either make a recommendation or not, rather than issue an 

“encouragement,” and he preferred that the recommendation be issued sooner rather than 

later. Dr. Orenstein pointed out that there already is a permissive recommendation to 

vaccinate the whole population, and 40-50% of the 2-49 year-old age group is already 

covered by existing recommendations. Whatever is decided, he suggested that the ACIP 

signal that influenza’s mortality and morbidity are unacceptable, and that strategy 

changes will periodically be reviewed, right up to considering full universal vaccination. 

• Dr. Wexler, of the Immunization Action Coalition, commented that the influenza vaccine 

is already recommended for 66% of the population. Since only 90 million doses are used 

(by half the population), the current approach clearly is not working well. Risk-based 

(e.g., for asthmatic children) recommendations are hard to implement and do not help 

families of 11-12 year-old children who die from influenza. She advised simply saying 

“The vaccine can be given to anyone who wants it.” She suggested that this approach 

would give health care providers the responsibility to offer the vaccine or to tell their 

patients about its availability (rather than having to ask for it), as was done for 

meningococcal vaccine before a full recommendation was issued. 

• Ms. Elisa Kanowitz, mother of Amanda, who died March 1, 2004, was very encouraged 

thatACIP was considering expanded recommendations. She supported the full 

recommendation, urging the committee members to “avoid analysis paralysis.” 

According to Ms. Kanowitz, the data are good, and more children like Amanda, Emily, 

and Jessica will die by next year. With more than enough vaccine next year, it should be 

recommended for the whole population. 

• Dr. Poland asked if the morbidity for the 2-5 year-old group was different from that of 

adult risk groups. Dr. Neuzil noted that Dr. Poland was raising an important point that 

had not been clearly addressed. Dr. Neuzil reported that morbidity is measured 

differently among children and adults, but one analysis of outpatient visit data found that

This document has been archived for historical purposes.
the results were almost identical to age 15, beginning at >2 years of age. According to 

Dr. Neuzil, the hospitalization data are probably the best proof of the higher rate of 

severe complications associated with influenza among those aged <5 years compared to 

those aged 5-49. But the rates in those aged <5 is driven a lot by children under 2 years 

of age. 

• Dr. Poland commented that, if the risk is the same, why parse out pieces of it? Dr. 

Abramson raised the feasibility issue as one reason. For example, access to children aged 

to 5-6 years is pretty good, and how to implement the recommendation in stages is part 

of policy considerations. 

Dr. Poland offered an Option 5, or Option 3+, to recommend vaccination for all Americans. 

Essentially, this proposal was Option 3 to recommend annual vaccination of children aged 24-59 

months, beginning in the 2006-2007 season, and encouraging everyone to get vaccine. “Annual 

influenza vaccination is encouraged for all Americans to reduce its related morbidity and 

mortality, work and school place disruption, and infection. It also aids pandemic preparedness, 

phased in over time. There also are specific age and condition recommendations. These groups 

should receive priority for vaccine.” 

Further discussion occurred which included Dr. Beck's clarification that there were two 

alternatives on the table, which did not include full recommendation, but recommended 

vaccination for those aged 24-59 months and encouraged vaccination for everyone else (i.e., 

universal), with the latter phased in. In his opinion, this effort was part of the strategy to move 

toward universal vaccination that was not committing ACIP to a time line, but was providing a 

goal to move toward. 

Dr. Lieu moved to recommend influenza vaccination for children aged 24-59 months, beginning 

immediately. It was assumed that vaccination of their household contacts and out-of-home 

caregivers was also included in this motion. Dr. Allos seconded the motion. In a friendly 

amendment, Dr. Poland moved an addendum to encourage all to be vaccinated for influenza 

as part of a strategy to achieve universal immunization. This was seconded by Dr. Allos. 

Dr. Gilsdorf asked the state health department representatives how the proposed recommendation 

would be received. Dr. Moore, of Tennessee’s health department, asked that the universal 

implementation be divided into pieces to avoid exceeding the vaccine supply, having to tier the 

recommendations, and struggling to reach the high risk populations. Dr. Morita agreed; 

Massachusetts’ situation would be the same.

Dr. Lieu reiterated the original motion to recommend vaccination for children aged 24-59 

months. No second was required as it had already been done. 

Vote 

Recommended influenza vaccination for children aged 24-59 months 

In favor: Allos, Beck Campbell, Finger, Gilsdorf, Lieu, Marcuse, Morita, Poland, 

Stinchfield, Treanor, Womeodu, Abramson 

Opposed: None 

This document has been archived for historical purposes.
Abstained: None 

The motion passed.

Dr. Poland moved to state that annual influenza immunization is encouraged for all as part 

of a strategy to achieve universal immunization. Again, no second was needed. 

Discussion: 

• Dr. Lieu supported the sentiment, but found the encouragement confusing, and remained 

concerned that it may disrupt state agencies’ work.

• Dr. Treanor was opposed, because it implied that ACIP had made a decision for universal 

vaccination in the absence of a discussion of data supporting the proposal, which he felt 

needed to occur. 

• Dr. Marcuse supported the sentiment, but he was reluctant to use “encouraged.” To 

achieve credibility, he wanted the discussion of a statement about a universal 

immunization vision to include vaccine efficacy and safety data; provider and consumer 

education; and, more information on efficacy and on herd immunity effects from 

vaccinating preschool versus school-aged children.

• Ms. Beth Rowe-West, of North Carolina, voiced her own and other program managers’ 

familiarity with the use of the word “encouraged” by now, and their support of universal 

vaccination. Dr. Moore, of Tennessee’s immunization program, also commented that the 

health departments would do less to implement this proposal than the private sector. She 

reported that in Tennessee, the health department provides only administers 10% of the 

influenza vaccinations; the private sector gives 90%.

Dr. Tan stated the AMA’s support of the language proposed. But to move the discussion along, 

he suggested, rather than saying "as part of an evolving strategy to move towards universal 

vaccination," saying "as part of an evaluation of a universal immunization strategy." He noted 

that his suggestion would loosen the language somewhat, but still allow encouragement of 

annual influenza immunization for all. Dr. Poland accepted that amendment and seconded it.

Further discussion noted that the concept of moving toward a universal influenza vaccination 

recommendation was not new; it was published in the MMWR ACIP influenza statement a few 

years ago, before Chiron had its production problems. There was lingering concern that next 

season’s influenza vaccine supply would be insufficient to meet the need for a full 

recommendation, and that even “encourage” implied that ACIP had reviewed all of the pertinent 

data.

Vote

Encouraging annual influenza immunization part of a strategy to achieve universal 

immunization

In favor: Allos, Campbell, Finger, Poland, Stinchfield, Treanor, Womeodu 

Opposed: Beck, Gilsdorf, Marcuse, Lieu, Morse, Morita, Abramson. 

This document has been archived for historical purposes.
Dr. Abramson voted no because that intent can simply be made part of the statement. He also 

remembered that recusals had not been checked. Dr. Treanor was uncertain if he had a conflict or 

not, as he had done a clinical study for ID Biomedical, which is now owned by GSK. Dr. 

Pickering stated that Dr. Treanor’s vote would be removed, but even without the recusal, the 

motion would have failed because it had failed to receive a majority of the votes. 

The motion failed. 

Dr. Marcuse summarized that there was clear enthusiasm for the concept, only division on its 

expression. Dr. Poland felt that he had achieved conceptually what he wanted. He remained 

unpersuaded by the fears expressed regarding the complexity of the current recommendations, 

and commented that if safety concerns are valid, the last vote should be revisited. His desire was 

to see ACIP move beyond its annual reactive role, and to state a laudable public health goal that 

all would support. 

Dr. Abramson summarized that the next statement would acknowledge that ACIP is working 

toward the goal of annual universal influenza vaccination in the U.S. He was not concerned 

about safety, but about other issues that all needed consideration. Dr. Poland agreed with that 

approach. Dr. Halsey cautioned ACIP about its recommend to discontinue the use of 

adamantanes for fear that the recommendation could prompt the manufacturers to stop making 

them. Dr. Halsey noted that adamantanes may be effective for other influenza strains. Dr. 

Abramson welcomed that point. 

Dr. Poland moved to state that a strategy of universal influenza immunization is being evaluated 

by the ACIP. The motion was seconded by Dr. Lieu. Dr. Stinchfield suggested placing a 

sentence near the end of the statement, to the effect that anyone who wants influenza vaccine 

should receive it. 

There was a vote on the statement, including tiering and incorporating Dr. Halsey’s point that the 

recommendation against the use of adamantanes is based only on current virologic susceptibility, 

which may change over time. The motion had already been seconded 

Vote

On the statement, including tiering and incorporating note that the recommendation 

against adamantanes’ use is based only on current virologic susceptibility, which may 

change over time. 

In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Lieu, Morse, Morita, Poland, 

Stinchfield, Treanor, Womeodu 

Opposed: None 

Abstained: None (there was no conflict involved in these aspects) 

The motion passed.

VFC Changes Relevant To Influenza Vaccine

Presenter: Dr. Greg Wallace, NIP

This document has been archived for historical purposes.
In past years, VFC only covered children at high risk and their contacts, and vaccine was left 

over even in years of shortage. Current changes to the VFC recommendation were: 

• A permissive recommendation for vaccine use among all those VFC-eligible children 

aged 6 months through18 years of age, with priority given to routine high risk groups 

when supplies are limited, and with the addition by ACIP in 2005 to add those with 

compromised respiratory function. 

• The first high risk group, 6 through 23 month-olds, will now say 6through 59 month-olds. 

• Contacts will change from those of children aged <2 years to children aged <5 years. 

• The language for LAIV will be added to the statement, "All healthy children age 5 

through 18 years with priority when supplies are limited to..." the contacts listed for 

TIV. 

• All currently licensed vaccines will be listed in the footnote.

Discussion included: 

• Vaccination will also be recommended for contacts of those children aged 24 through59 

months. 

• Dr. Poland asked if there were any new data on anaphylactic reactions due to chicken 

allergy, since that evidence was found to be outdated for MMR. No one had that 

information; the influenza working group will look into it. If it cannot be determined for 

this year, it will be addressed next year. 

Dr. Finger moved to approve the VFC resolution with the changes described. Dr. Poland 

seconded the motion. 

Vote

In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Lieu, Morse, Morita, Poland, 

Stinchfield, Treanor, Womeodu, Abramson 

Opposed: None 

Abstained: None (there was no conflict involved in these aspects)

The motion passed.

Update on HHS Pandemic Influenza Planning 

Presenter: Dr. Bruce Gellin, Director, NVPO

A national strategy for pandemic influenza was released by the President on in November 1, 

2005, and the Department of Health and Human Services (HHS) pandemic influenza plan was 

released the next day. The implementation preparedness plan for activities across the federal 

government will soon be released. Preparedness activities for seasonal influenza and pandemic 

are aligned. 

Of the $7.1 billion proposed for pandemic preparedness, $6.7 billion was for HHS. Congress 

provided $3.3 billion in December, and the President's budget for 2007 proposed another $2.3 

billion for this coming year (the second year of funding of the original budget plan). 

This document has been archived for historical purposes.
Federal Roles.

• The largest aspect of preparedness is the creation of a stockpile in bulk of 20 million 

courses (2-doses) of vaccine against the most likely pandemic threat, by February of 

2006 (currently there are 8 million doses of H5N1 vaccine, at 90 mg/dose). 

• Creation of a domestic influenza vaccine manufacturing capacity sufficient to produce 

300 million courses within 6 months of a pandemic onset is being examined; as is 

increasing egg-based capacity and accelerating cell-based production capacity,

retrofitting existing manufacturing facilities for emergency influenza vaccine production, 

accelerating the development of dose sparing techniques (e.g., adjuvants, immune 

stimulants, delivery technologies), and developing a broad spectrum influenza vaccine.

• A Request for Information (RFI) was posted on January 30, 2006, regarding efforts to 

expand existing egg-based influenza vaccine manufacturing facilities, to build new 

facilities, to convert existing manufacturing facilities that produce FDA-licensed 

vaccines and biologics to produce influenza vaccines, and to advance the development of 

recombinant-based influenza vaccines. Responses are due in February. 

• The goal of the Strategic National Stockpile (SNS) of antivirals is to be able treat 25% of 

the U.S. population with antivirals (75 million treatment courses), reserving another 6 

million for containment uses. There is full funding for 50 million doses and to subsidize 

the states’ 25% of the remaining treatment courses. 

• An RFI was posted last year, and some responses have been received, to develop new 

prophylactic or therapeutic agents to prevent or treat influenza virus infection. With the 

resistance to adamantanes, only neuraminidase inhibitors are left as treatment. The 

treatment criteria include shelf life, efficacy, bioavailability or half life, and, oral or 

parenteral delivery.

• More than 100 subject matter experts at CDC are working on pandemic preparedness. 

State roles. The states were allocated $350 million in the recent emergency pandemic influenza 

appropriation passed by Congress in December. Each state will receive at least $500,000, with 

additional funds allocated by population. New York City, Chicago and Los Angeles County will 

receive supplemental grants. The balance of the $250 million appropriated will be awarded later 

in 2006 based on progress and performance. States and municipalities will use these funds to 

accelerate and intensify current planning efforts for pandemic influenza and for plan exercises. 

Other FY06 budget priorities include expansion of FDA’s regulatory science base, enhancing the 

SNS (with personal protective equipment, ventilators, etc.), increasing CDC's influenza lab 

capacity, expanding domestic biosurveillance and situational awareness, advancing the 

development of rapid diagnostics, and expanding education and risk communication activities. In 

addition, the U.S. contribution of global pandemic preparedness is $334 million. 

NIH/NIAID H5N1 Update

Presenter: Dr. George Curlin, NIAID/NIH

Trials. Of NIH’s current >100 ongoing active clinical trials, >33% are exploring a pandemic 

strain vaccine. Vaccine options include inactivated vaccines similar to TIV, live vaccines similar 

to LAIV, and inactivated vaccines with novel adjuvants and routes of administration. Inactivated 

This document has been archived for historical purposes.
vaccine has a proven technology and the largest manufacturing capacity, and its licensing would 

be simpler. Multiple doses probably will be required. 

Safety/Efficacy. Past experience with H5 vaccine development includes the response to the initial 

Hong Kong outbreak. The Hong Kong H5-based vaccine is predictive for the current vaccine 

trials (i.e., higher doses give a better response, but all doses give some response.) Second-dose 

data are needed. The current trial of the rgA/Vietnam1203/04 (H5N1) vaccine involves healthy 

adults ages 18-64 years in a prospective, randomized, double blind study. Two intramuscular 

(IM) doses are given at a 28 day interval. The antigen range is broad, from 7.5 to 90 mcg, and 

the end points are safety and immunogenicity (neutralization titer of 1:40). To date, the vaccine 

has been well tolerated, producing some neutralizing responses at all doses, but the highest doses 

gave the best response (a 45–90 mcg dose was “acceptable”). 

Immunogenicity. Several strategies are being explored to overcome poor vaccine 

responsiveness: administering a priming dose, incorporating adjuvants, and using alternate 

administration methods including intradermal (ID) vaccination. In Europe, 30 mcg doses of the 

H5 formulation have been found effective with an alum adjuvant, but in normal interpandemic 

vaccines used at NIH, the alum has poorly enhanced immunogenicity. The current study (DMID 

05-0217) is a dose ranging study on a constant alum vaccine formulation among healthy adults. 

The MF59, a proprietary adjuvant in use, has been promising. 

Route of delivery. Intradermal vaccination was studied previously, comparing 15 mcg delivered 

IM versus 6 mcg delivered ID. The latest study compares 3 mcg and 9 mcg ID. No difference 

was seen in the previous study in those persons aged 18-60 years, but the IM delivery was much 

more effective than ID in those persons aged >60 years. 

Formulation. Studies of live attenuated vaccines are also underway, and some cold-adapted H5, 

H7, and potentially pandemic strains have been developed. These vaccines are of interest 

because they are highly immunogenic in susceptible populations (although correlates of 

protection need to be defined); they can potentially be used at low doses, and their induction of 

mucosal immunity might reduce transmission. They also may offer some cross protection. 

However, they are not licensed in all population groups; more safety data are needed; as are 

correlates of immunity that could be extended to the elderly. Other concerns involve issues of 

transmission and reassortment. 

The experimental pandemic vaccines include nasal inactivated vaccines, cross-protective 

peptides and epitopes, virus-like particles, alternative live vaccines, vectored approaches, and 

DNA vaccines. But the current critical question in the search for a pandemic vaccine is whether 

the H5 hemagglutinin is intrinsically less immunogenic in humans. Its biological mechanism is 

unclear. NIH is awaiting Australian data which reportedly indicate a good vaccine with an alum 

adjuvant, based on the Vietnam strain. 

The vaccine development pipeline to date includes: 

• Sanofi pasteur and Chiron have submitted the current vaccine trial data for publication. 

Higher doses generated acceptable response. There are data on healthy adults and 

ancillary populations are already under study. 

This document has been archived for historical purposes.
• Sanofi pasteur’s vaccine trials have completed enrollment in the elderly study, and 

enrollment is underway for the children’s study. Sanofi pasteur’s H5N1 vaccine with 

adjuvants is being studied among healthy adults (DMID 05 0127) and older adults 

(DMID 05 0141). 

• Chiron’s H5N1 M59 was very immunogenic with the H9 strain. They are awaiting an 

import license to begin trials.

• A booster dose to the current two-dose H5N1 vaccinees with the sanofi pasteur H5N1 

vaccine is being done to assess its benefit.

• Also planned, but on hold, is a study to add the H5N1 to the routine annual vaccine for 

healthy adults. 

Discussion included a question of how far in advance a vaccine can be developed before the 

virus has been identified as a pandemic strain; whether the 20 million vaccine doses for the 

stockpile will be developed before then; and, if so, what was expected of the vaccine’s efficacy. 

Dr. Curlin responded that the Vietnam strain, which has spread to Eastern Europe and Africa, is 

apparently fairly stable. The hope is that this virus will sufficiently protect from any new strain, 

should a pandemic occur. Dr. Gellin added that the annual influenza vaccine formulation also is 

based on the most recent strain, hoping that this would provide cross-protection to any strain 

deviation. But should a new strain emerge, a new vaccine would have to be developed. This 

situation is occurring currently, where a prototype vaccine is now being developed using one 

selected clade of the two current H5N1 clades. Slightly less than 8 million doses have been 

manufactured this year by sanofi pasteur and Chiron; the pandemic vaccine cannot be 

manufactured until production of the annual strain ends. As a result, commercial scale 

manufacturing of the pandemic strain will have to wait until next fall. But with increased 

manufacturing capacity, the prepandemic vaccines perhaps could be made while the companies 

produce the annual vaccine. 

TETANUS-, DIPHTHERIA TOXOID, ACELLULAR PERTUSSIS VACCINES

Report from the Pertussis Working Group 

Presenter: Dr. Dale Morse, Pertussis Working Group Chair

Overview: Review of ACIP Pertussis recommendations 

The ACIP recommended protecting adolescents aged 11-18 years against pertussis in June 2005, 

by giving one dose of Tdap rather than Td. The Tdap dose was encouraged even if the Td had 

already been given. An interval of >5 years between Td and Tdap also was encouraged, but 

shorter intervals could be used. In October 2005, the Working Group discussions of a 

recommendation for adults aged 19-64 years produced the following suggestions: 

1. Adults aged 19-64 years should receive a single dose of Tdap, in place of the next Td, to 

reduce pertussis among adults and reduce transmission of pertussis to infants. An interval 

<10 years since the last Td can be used for booster protection against pertussis. The 

safety of an interval as short as ~ 2 years between Td and Tdap is supported by a 

Canadian study. 

2. Adults who have or will have close contact with an infant <12 months of age (e.g., 

This document has been archived for historical purposes.
parents, grandparents, childcare providers, health-care workers) should receive a single 

dose of Tdap at an interval shorter than 10 years since the last Td, to protect against 

pertussis. Ideally, they should be vaccinated ≤1 month before close contact with the 

infant. (Cocooning) 

3. Interim guidance regarding pregnancy was: “Women should receive a dose of Tdap in the 

immediate post-partum period if they have not previously received Tdap.” 

On this day, the Working Group presented the issues related to Tdap use among health care 

workers and adults aged >64 years. In June, presentations are scheduled on the issues related to 

the use of Tdap among pregnant women (adolescents and adults), and an ACIP statement on that 

will be proposed. 

The purposes of Tdap vaccination of adults are to: 

1. Protect them from pertussis morbidity.

2. Decrease pertussis exposure to persons at increased risk of severe pertussis and its 

complications, especially infants aged <12 months and adults with co-morbid conditions. 

3. Reduce the cost and disruption of pertussis in institutional settings. 

4. Reduce the reservoir of pertussis. 

Considerations related to these objectives are that Tdap is licensed as a single-dose vaccine. Its 

duration of immunity wanes at ~5-10 years after vaccination and infection, which makes the 

need for a ~10-year Tdap booster probable. Finally, the vaccine could cost ~$20 more than Td. 

Tdap is expected to be effective in stopping transmission, but how that will be shown in the 

population is unknown. Currently, Td coverage among adults aged 19-64 years is low, at 

only~55%-67%, and is ~42% among in those aged >65. Tdap is not licensed for use in those 

aged >65 due to a lack of data to support that. 

The Working Group advised ACIP to recommend Tdap at a short interval after the last Td for 

healthcare workers with direct patient contact in hospitals or ambulatory care settings, and to 

allow permissive use of Tdap among adults aged >64 years, even thought this is an off-label use.

Manufacturer Updates 

• sanofi pasteur Dr. Michael Decker reported that Sanofi Pasteur is revising study 

protocols to provide data in ~3 years that will support licensure of AdacelTM with no 

upper age limit. Study enrollment is under way in Germany to assess AdacelTM given as 

the sixth consecutive dose of acellular pertussis vaccine; the five previous doses were 

given as Tripedia®. A similar AdacelTM study will be done with U.S. and Canadian 

cohorts as soon as they age to the lower age limit for AdacelTM, expected in ~1 to 11⁄2 

years. A safety study of repeated AdacelTM administration will be done in a population 

that first received AdacelTM ~41⁄2 years ago to provide an evaluation of the safety of readministration after a 5-year interval. 

• GSK. Dr. Friedland reported post-marketing studies are underway of Boostrix® coadministered with MCV4. GSK is working with FDA to expand the licensed indication 

for Boostrix® beyond aged 18 years of age. A study of six consecutive doses with 

Boostrix® has been completed and is described in the package insert.

This document has been archived for historical purposes.
Tdap Use Among Adults Aged >65 Years

Presenter: Dr. Katrina Kretsinger, NIP

Overview: Review of the scientific rationale for permissive-use of Tdap among adults 

>65 years of age, the current standard of care, considerations from the program 

perspective, and proposed wording. Older American adults have the highest tetanus case 

incidence and mortality; improving vaccination against tetanus and diphtheria is 

important. 

Vaccine. AdacelTM (Tdap), made by sanofi pasteur is licensed for use among persons from age 

11 to 64 years as single-dose booster immunization against tetanus, diphtheria, and pertussis. 

ACIP recommended Tdap use in that age group. AdacelTM also is the only Tdap licensed for use 

from age 19-64, as GSK’s Boostrix® is licensed for ages 10-18. There are no prelicensure safety 

or immunogenicity studies for AdacelTM use among adults >65 years (older adults) who in 2002 

comprised 12% of all Americans (~36 million). 

Pertussis disease burden. No prospective population-based study data exist on pertussis 

incidence among older adults, but pertussis is probably under-reported, as it is among younger 

adults. In a serosurvey of 100 adults aged ≥65 years tested every four months for three years,,10 

developed B.pertussis infection as measured by antibody rise, and half of those infected 

developed cough illness (Hodder CID. 2000;31:7-14). 

Data of the National Notifiable Disease Surveillance System (NNDSS) from 1996-2004 were 

examined. In that period, 894 cases of pertussis were reported among older adults; of these 8% 

were hospitalized and x-rays indicated that 12% had pneumonia, a higher rate than that reported 

for adults or adolescents. Four patients died, all of whom had co-morbidities. 

A 1992 pertussis outbreak in a Dutch religious institution had a 53% attack rate of laboratoryconfirmed clinical pertussis in its older residents, four of whom died from pertussis-associated 

causes (Mertens, Eur J Clin Micro. 1999; 18:242-247). The attack rate in a 1985 Wisconsin 

nursing home outbreak was 36% (Addiss, JID. 1991; 164:704-10). 

Pre-licensure safety and immunogenicity data among adults 19 to 64 years of age were examined 

(in the absence of prelicensure data for older adults). Also reviewed was preliminary data of an 

Austrian study of Tdap administered with IPV among older adults, and VAERS reports. 

• Td506. The principal AdacelTM safety and immunogenicity study Td506, randomized 

persons aged 11-64 years to receive either sanofi pastuer Td or Tdap (both have the same 

diphtheria and tetanus toxoid quantities). Data were gathered for four pre-defined age 

groups (11-17, 18-28, 29-48, 40-64), as well as from an ad hoc subset of adults aged 60-

64 years. 

• Td506 safety data were charted for local reactions (pain, erythema and swelling) for the 

four age groups from vaccination to 14 days later. Reports of pain decreased with the 

recipients’ increasing age, rates of erythema and swelling were constant, and fever rates 

were generally lower for adults than adolescents. Serious adverse events (AE) were 

followed for six months, and were 1.9% for both Td and Tdap recipients. The U.S. 

This document has been archived for historical purposes.
AdacelTM prelicensure safety studies had two serious adverse events that were possibly 

related to Tdap; both resolved without sequelae. 

• Unpublished Austrian Tdap-IPV combination vaccine (RepevaxTM) immune-response 

study data were reviewed. RepevaxTM has the same Tdap composition as Adacel.TM The 

study enrolled 252 healthy adults aged 59-91 years; all had had Td boosters but no 

pertussis vaccine. They received one dose of RepevaxTM. Pre-defined immunogenicity 

and safety endpoints were not primary study objectives. Written AE reports were solicited 

5 weeks after vaccination (recall that in Td506 AEs were solicited at 14 days after 

vaccination. The Austrian cohort on average were older (59-91 years) than the Td506 

cohort (48-64 years), and had about half the AE rates found in Td506. Comparison of the 

two studies should be interpreted with caution because these studies were conducted 

under different protocols, by different investigators, and using different evaluation 

criteria. 

• VAERS is a national, passive surveillance system for reporting adverse events following 

vaccination. No disproportionate rate of adverse events among older adults is reported 

after Td and TT among older adults compared with younger adults (Lloyd JC et al.

Vaccine 2003; 21). Reports of Guillain Barré Syndrome (GBS) and extensive limb 

swelling are rare after Td in older adults.

• Immunogenicity to tetanus and diphtheria toxoids after Tdap. Immune responses to 

tetanus and diphtheria toxoids were reviewed separately from immune responses to 

pertussis antigens because the serologic correlates of protection for tetanus and diphtheria 

are defined, Tdap was seroprotective against tetanus and diphtheria and the boosterresponses met the noninferiority criteria for Td among adults aged 11-64. Presented 

tables showed unpublished data for adults aged 60-64 years, demonstrating the same high 

seroprotection for Tdap as for Td. Although the response to tetanus and diphtheria toxoids 

was adequate from age 49-65 years, antibody responses to both toxoids declined with 

advancing age.

• Immunogenicity to pertussis antigens after Tdap. Serological correlates of protection for 

pertussis are not well accepted. The Tdap (AdacelTM) licensure for 11-64 year-olds was 

based on inferred efficacy from the boosting response in adults with serologic bridge to 

the immune response to three doses of DTaP among Swedish infants. 

• Pre- and post-vaccination geometric mean titers (GMTs) from older adults in the Austrian 

study of Tdap-IPV were compared with results from the ad hoc subset of adults aged 60-

64 years from Tdap arm of the U.S. principal pre-licensure study (Td506). Both studies 

showed older adults had an immune response to pertussis antigens. In the principal prelicensure trial Td506, the GMTs by age category showed that levels of filamentous 

hemagglutinin and pertactin remained relatively constant with increasing age, but levels 

of pertussis toxoid and fimbriae 2 and 3 declined with increasing age. 

In summary, the pertussis burden among older adults is not well defined but likely substantial. 

No U.S. trials of Tdap have been conducted among older adults, but other related data do not 

suggest safety concerns; AE rates are similar or decline with increasing age. Based on results 

among aging younger adults, tetanus and diphtheria immunogenicity are likely to be similar after 

Tdap and Td for older adults, but data specific to this group are lacking. 

The rationale for permissive use of Tdap include the following: use of Tdap is consistent with 

This document has been archived for historical purposes.
and would reinforce the existing standard of care for the recommended tetanus and diphtheria 

decennial booster, Tdap would provide pertussis protection standard for care for older adults who 

are in contact with infants (e.g., grandparents or be healthcare workers), and Tdap would allow 

programmatic flexibility and provide guidance for clinicians. 

The disadvantages of permissive use of Tdap include the increase in cost over the cost of Td for 

older patients, and that its use would be off label. In the past, the ACIP has made off-label 

recommendations for special populations and vaccine situations, such as use of Haemophilus 

influenzae type b conjugate vaccine for immunocompromised adults, and use of DTaP at age 12 

months (given a 6-month interval) for a child unlikely to return for the 4th dose scheduled at 15 

to 18 months of age. Some past ACIP vaccine recommendations included routine use among 

older adults when the vaccine was licensed without upper age restriction (e.g., influenza vaccine, 

Td, and PPV-23). 

The working group proposed permissive use of Tdap among older adults, to be accompanied by 

information describing available safety and immunogenicity data, and information to ensure that 

the standard of care for tetanus and diphtheria are maintained through use of either Td or Tdap. 

The working group also proposed that ACIP include a specific recommendation for additional 

studies on Tdap safety and immunogenicity among older adults as a basis for any future 

recommendation. 

Proposed recommendation. The suggested wording was as follows: 

“Tdap is not licensed for use among adults >65 years of age. The safety and 

immunogenicity of Tdap among adults >65 years of age were not studied during U.S. 

pre-licensure trials; data from clinical trials among older adults are limited (see section, 

Tdap among Older Adults). Clinicians can choose to administer Tdap to adults >65 years 

of age for protection against pertussis in addition to protection against tetanus and 

diphtheria. 

“Recommendations for use of Tdap in adults >65 years will be updated as new data 

become available.

“All adults, including adults >65 years of age, should receive a dose of tetanus toxoidand diphtheria toxoid-containing vaccine every 10 years for protection against tetanus 

and diphtheria, and as indicated for wound management.” 

(Areas of future research related to Tdap and adults): “... Studies are needed to 

establish the safety and immunogenicity of Tdap among adults aged >65 years to support 

an evidence-based recommendation for use of Tdap among older adults...” 

Discussion included points in favor of permissive use of Tdap in older adults: 

• Dr. Plotkin appreciated, to general agreement, the cocooning strategy of protecting infants 

by vaccinating parents and grandparents. 

• Dr. Schaffner advised against limiting Tdap by age group, which risks further confusing 

internists and the public. Although the issues of safety and immunogenicity need to be 

This document has been archived for historical purposes.
addressed, he thought them unlikely to be substantive, and few internists would hesitate to 

give Tdap to patients aged 66 as well as 64. 

• Both Dr. Decker and Mr. Hosbach said ACIP’s decision would not affect their plan to 

study Tdap in older adults. They anticipated it will require 2-3 years to complete the 

study and obtain FDA licensure. 

• Dr. Tan liked the permissive language and favored letting physicians choose, especially 

since the following text states that recommendations will come, pending data. 

Points opposed to permissive use of Tdap in older adults included: 

• Dr. Baylor commented that this recommendation varies from the FDA-approved label, 

which was based on the available data. He noted that studies have begun or are ongoing in 

these populations, and data will be available sooner rather than later. Additionally, the 

proposed recommendation is generic for Tdap, not a specific product. The GSK product 

is licensed only to age 18, a big difference to age 64. (Dr. Kretsinger noted that the 

recommendation for adult Tdap use only applied to one product, Adacel,TM and that this is 

clearly stated in the adult recommendations.)

• Dr. Abramson commented that ACIP only has recommended off-label when there was no 

chance of getting the needed data, something not the case here. Dr. Lieu agreed.

• Dr. Pickering commented on the very small number of participants in the studies, none of 

whom were in the full targeted age group, and the great difference in the U.S. and 

Austrian studies. He found the recommendation to be too subjective. He agreed with 

other comments that the studies are being done and clinicians already can vaccinate this 

older age group against pertussis if they so choose. 

• A permissive use statement would not tell internists they shouldn’t use the vaccine but 

rather that it would state that evidence supporting use of the vaccine among older groups 

is not available. Regardless, discomfort with a “recommendation” contrary to FDA 

licensure remained, Further, few studies provide evidence that older adults are an 

important source of pertussis for infants, which leaves the benefit of vaccinating older 

adults hypothetical for cocooning. Similarly, few or no studies provide evidence that older 

adult care providers are a source of pertussis for infants in child daycare. 

• Neither Td nor Tdap is paid for by Medicare for preventive care. 

• Dr. Pickering recalled the DTaP/Hib vaccine discussion when permissive off-label use of 

DTaP/Hib was released. He indicated that if a statement like this had been released, 

hundreds and maybe thousands of children would not have been properly immunized 

again Hib. 

• Dr. Jeff Duchin, of NACCHO noted that the pertussis burden of disease is not significant 

in older adults, nor a large factor in transmission, negating any urgency to recommend at 

this time.

Alternatives suggested were: 

 Dr. Campbell suggested deleting the last sentence of “Clinicians can choose to 

administer...” and the next two paragraphs about updates and the decennial booster. She 

proposed adding, “We recognize that vaccinating this population will likely be important 

to full implementation of a cocoon strategy.” 

 Dr. Wexler suggested saying, “While not specifically recommended by ACIP for use, or 

licensed by FDA at this time, clinicians can choose to administer...” 

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 Dr. Temte urged caution, especially in view of ACIP’s development of evidence-based 

classifications for its recommendations. He had heard no data on rates of transmission 

between grandparents and infants; and the pending product is for adolescents, the highest 

transmission group. Clinicians have the right to treat as they see fit, but they look to 

ACIP for evidence-based guidance.

Dr. Finger moved to amend the proposed recommendation language by striking the 

sentence beginning with the word “Clinicians...” The motion was seconded by Dr. Campbell.

Dr. Morse reported the Working Group’s minor concern about safety in this age group, and wish 

for more of a science base of exposed children. But they concluded that the sentence does not 

really matter, since physicians can vaccinate anyway as soon as it is licensed. 

Dr. Allos observed (and Ms. Stinchfield agreed) that if the “clinicians...” sentence is dropped, 

the recommendation would read more like a caution against using the vaccine in people aged 

>65. Waiting to weigh the benefits and risks may do more harm. She suggested saying, “The 

ACIP would like to recommend use of this vaccine in those aged >65, but cannot do so until data 

are available. That is anticipated in ~2 years.” That would convey this as an option to physicians 

about the newborn as well as to grandparents. 

Vote 

To approve the amended recommendation text.

In favor: Campbell, Finger, Gilsford, Lieu, Marcuse, Morita, Abramson 

Opposed: Morse, Poland, Stinchfield, Womeodu 

Abstained: None 

The motion carried.

Tdap Use Among Healthcare Workers

Dr. Tejpraptap Tiwari, NIP 

Overview: Rates of pertussis among health care workers, transmission in health care 

settings; related costs.

Protecting the 8-10 million U.S. healthcare workers from acquiring and transmitting infectious 

diseases is a public health goal. Adult pertussis morbidity is substantial and includes cough for 

≥3 weeks for 80%-100%. It can cause urinary incontinence in ~39% of women, rib fractures in 

~4% of adults, and syncope in ~3%. Although data describing the incidence of pertussis among 

health-care workers are limited, a few studies have been conducted. Four were outlined: 

1. Of 93 pediatric hospitals surveyed in 1994 by Lane et al (ICHE 1997;18:400), 90% of the 

62 respondents reported cases of pertussis within the past 5 years. Of those, 11% reported 

one or more physician contracted pertussis after exposure to a patient; data on other 

health care workers was not reported. 

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2. Deville et al (CID 1995; 21(3):639) reviewed conducted annual serosurveys for pertussis 

from 1984-1989 in a tertiary care hospital. Fifty-one health-care workers were infected 

(based on elevated anti-PT titer) for a mean annual rate of 8%, and range from 4%-16%. 

Re-infection was common. The rate of symptomatic pertussis was not reported. 

3. Wright et al (ICHE 1999; 20[2]:120-3) conducted a serosurvey of 145 health-care 

workers in a 660-bed tertiary care hospital from 1992 to 1994. Sera were obtained from 

emergency department (ED) personnel and resident physicians. The rate of symptomatic 

infection was 40%. Recent infection occurred among 7.6% of ED personnel and 2% of 

residents. The annual incidence of pertussis among ED personnel was 3.6/100 personyears and among residents was1.3/100 for residents. 

4. De Serres G.( J Infect Dis 2000;182:174) found a 1.7-times increased risk of pertussis 

among health-care workers in Quebec compared with the general population. Eight 

percent of adult pertussis cases from July to December 1998 were among health-care 

workers, even though health-care workers comprised only 5% of the adult population 

Health-care worker role in transmission. CDC data indicate that a wide range of positions 

among health-care workers acquire or transmit pertussis, but they have in common direct contact 

with patients and direct contact with other healthcare workers. The two primary factors that 

foster transmission are delayed diagnosis and treatment in the source case, and late 

implementation of control measures. The intensity of contact has varied by setting. Outbreaks in 

each were described, for hospitals’ pediatric and adult settings, ambulatory care pediatric and 

adult settings, and a long-term residential care facility for developmentally disabled adults. A 

table of reported pertussis outbreaks in pediatric settings (13 studies) showed three outbreaks 

beginning with a health care worker; two beginning with infant to health-care worker, and 8 

beginning with an infant with pertussis. Although 7 pertussis outbreaks in adult-care settings had 

health-care workers for all the index cases, in three of four long term care residential facility 

outbreaks patients were the index cases in three, and the index case was not identified in one. 

Six studies of health-care workers with pertussis in pediatric hospitals showed cases transmitted 

by health-care workers before the illness was recognized. The majority of secondary cases were 

among health-care workers. However, secondary cases among infants occurred and resulted in 

substantial morbidity, e.g., an infant with hospital-acquired pertussis required mechanical 

ventilation for >2 weeks and required another 2 months of hospitalization. When pertussis was 

recognized, investigation identified a large number of contacts who required post-exposure 

prophylaxis. In one outbreak (Martinez et al) the number of cases and contacts was so large that 

the hospital chose to give chemoprophylaxis to 3179 employees. Four studies (Jankelovich, 

2006; CDC, 2005; Friedman, 2005; and McCall, 2002) described health-care workers and patient 

exposures in adult-care settings that began with a single health-care worker; secondary cases 

were prevented by existing control measures. 

Costs. Pertussis control guidelines (CDC/HICPAC, MMWR 2003; HICPAC, AJIC 1998; CDC 

2000) advise hospital infection control practitioners identify close contacts, provide postexposure prophylaxis, test and treat symptomatic employees and patients, and furlough 

symptomatic employees for the first five days of treatment. These activities are labor intensive 

and costly. The charted costs of outbreaks at three hospitals (general, general with adult and 

pediatric beds, and pediatric) ranged from $64,000 to $106,000 in direct costs; from $3500 - 

This document has been archived for historical purposes.
$21,000 in cost per case; $97-$144 per exposure. Indirect costs for personnel hours lost ranged 

from $11,000 to $68,000, and $97-$180 in per case. Total costs ranged from $75,000-$174,000. 

Cost-Benefit Analysis of Tdap Vaccination of Health-Care Workers 

Presenter: Dr. Ismael Ortega-Sanchez, NIP

Overview: Analysis of potential cost savings from preventing pertussis among vaccinated 

health-care workers, without change in control practices (given that Tdap’s effectiveness 

to prevent subsequent transmission from vaccinated health-care workers is unknown). 

Pertussis in health-care workers and nosocomial pertussis outbreaks are a special concern in 

health-care settings because transmission can occur to patients vulnerable to severe pertussis. 

Vaccinating health-care workers will prevent the morbidity of pertussis. In addition, vaccinating 

health-care workers may 1) reduce pertussis infections and outbreaks in hospitals, 2) decrease 

transmission and prevent secondary cases, and thereby reduce outbreak size and duration, and 3 )

reduce the infection containment costs. The last includes case- and contact tracing, post-exposure 

prophylaxis, and/or treatment of hospital-acquired pertussis cases 

To determine if cost savings might be possible from a program to vaccinate health-care workers 

against pertussis, a probabilistic model was used assuming 1000 hypothetical health-care 

workers with direct patient contact, followed for ten years. Probability distributions were 

specified for key parameters using a range of values, and varied simultaneously using Monte 

Carlo simulations. Results were reviewed for the following outcomes: number of nosocomial 

pertussis exposures; vaccination-produced net costs or savings from prevented pertussis, 

according to a hospital perspective. Health costs and benefits were calculated in 2004 dollars 

with a 3% discount rate. Net costs (or savings) accrued to the vaccination program and benefitcost ratios were estimated. 

Model assumptions: The model assumed 1) no change in post-exposure control measures, 

including antimicrobial prophylaxis, and 2) an annual turnover rate of 16% of the 1000 healthcare workers, and 20% of the original cohort left by year 10. To maintain a stable population in 

the model, those leaving each year were assumed to be replaced by new, mostly unvaccinated 

healthcare workers. In the model, 66% of health-care workers were vaccinated at the beginning 

of the first year. Since some health-care workers who were vaccinated would leave, to maintain 

protection levels would require vaccination of new health-care workers at the beginning of each 

year. This progression was outlined on a decision analysis chart, which also included possible 

vaccine failure, and subsequent exposures. 

The literature provided values and ranges for the annual rate of B. pertussis infection in healthcare workers, the proportion of these infections that would be symptomatic, the number of 

hospital contacts exposed by each symptomatic health-care worker, and infection control costs 

per exposure. The cost estimates were comprehensive, including contact tracing, laboratory 

work, antimicrobial treatment and health-care worker furloughs. The literature provided data on 

vaccine efficacy and coverage, adverse events, vaccine cost, as well as the mean values for 

employee turnover rates, etc. 

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Algorithms used to calculate the annual number of pertussis exposures prevented, or not, per 

1000 healthcare workers, with- and without a vaccination program were described. Exposures 

were defined as the number of patients and health care workers in the hospital who had direct 

contact with the persons with pertussis. The number of exposures prevented was the proxy for 

the number of cases prevented. 

Results. After the Monte Carlo simulations of the number of exposures resulting from health-care 

workers ill with pertussis, we selected the median number of exposures and approximated a 

confidence interval using the 5th and 95th percentile simulation values. With the Tdap vaccination 

program in health-care workers, we estimated that a median of 93 (46%) of annual exposures 

would be prevented, with a range of 13-310 exposures (5th and 95th percentiles). The calculated 

net containment costs saved in a ten year period (cost of infection control less vaccination costs, 

both discounted) was $94,981 per 1000 health care workers, with a range of a negative $52,882 

(5th percentile) and a positive $534,807 (95th percentile). The benefit-cost ratio of a Tdap 

vaccination program from a hospital perspective was a $2.38 return for every dollar invested in 

the vaccination program for health-care workers ($0.36-$10.86). 

Sensitivity analyses. A multivariate regression analysis was done over the range of simulation 

estimates to gauge the analysis’ sensitivity for pertussis exposures prevented and the benefit-cost 

ratio. The statistically significant variables in order of their influence over the model outcome 

were the number of exposed health-care workers, the incidence of pertussis among health-care 

workers, employee turnover and cost of the vaccine (both with a negative influence), vaccine 

coverage and efficacy, and containment costs.

A line graph demonstrated the impact of symptomatic rates and the incidence of B. pertussis

infection on the benefit-cost ratio. Net vaccination cost-benefits were achieved at a 6.7% 

incidence rate, if ≥15% of health-care workers are symptomatic, at 3.6% incidence rate if >28% 

of health-care workers are symptomatic, and at 2.5% incidence rate if >40% of health-care 

workers are symptomatic. 

Threshold analyses were done to determine breakeven values for ten variables, of which three 

were highlighted: vaccine cost per dose, number of contacts exposed, and the health-care worker 

turnover rate. If other factors were not changed, net savings from a vaccination program were 

possible if, for example, the number of exposed contacts per health-care worker was > 2.5 rather 

than 8.73 as in the base-case, if the health-care worker turnover rate was >100% rather than 16% 

as in the base-case, or if the vaccine cost was $84 rather than $30 as in the base-case. 

Limitations of the analysis included the use of exposures as a proxy for potential cases, possibly 

limited generalizability of the results, the assumption of an inverse correlation of vaccine 

effectiveness and coverage with the number of exposures and outbreaks, an assumed constant 

ratio of health-care workers-to-beds, and an assumed constant hospital occupancy rate. The 

model’s strengths included 1) the assumed turnover rate and continuous vaccination reduced the 

relevance of prolonged vaccine effectiveness, and 2) the probabilistic modeling and threshold 

analyses identified key uncertainties for future research.

Conclusions were that:

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• A Tdap vaccination program in health-care workers could have substantial impact in 

reducing hospital-acquired pertussis morbidity by reducing the number of annual 

exposures (-46%).

• The benefits (or savings) from a Tdap vaccination program could be sizable for hospitals 

even after covering program costs (the benefit-cost ratio could be >1). 

• Health and cost outcomes are highly sensitive to the number of persons exposed in the 

hospital per each symptomatic health-care worker, the annual rate of B. pertussis

infection in health-care workers, and the proportion of workers who become 

symptomatic.

Discussion included: 

• The vaccine cost per dose was for vaccine only, not the program. Dr. Marcuse noted the 

far greater cost of a program, to which Dr. Ortega-Sanchez agreed. But even with an $84 

total cost, there could be benefit to the hospital. Dr. Hull added that the vaccination 

would be added to systems already in place to deliver other vaccines, so the increment 

would be far less than that of a new program. 

• Ms. Stinchfield noted that Dr. Tiwari’s tertiary care hospital slide indicated 40% of adults 

are symptomatic with B. pertussis infection. That could include nasal carriage, but 

asymptomatic persons do not transmit.

• The base case incidence in health-care workers was based on the serological studies 

presented, which came from in-house serologic analysis of antibody titers to determine 

the annual infection incidence range of 4%-16%. 

• Dr. Lieu commented that the presentations inferred a “slam-dunk” recommendation 

decision. She asked for any areas of controversy. Dr. Murphy identified two: the weak 

national data on incidence rates, among health-care workers, although outbreaks are well 

defined; and the unknown level of transmission prevented in vaccinated health-care 

workers. The vaccine may be efficacious against disease, but even a mild cough or 

respiratory symptoms may transmit.

Proposed Tdap Recommendations

Presenter: Dr. Trudy Murphy, NIP 

Overview: Rationale for recommending Tdap for health-care workers with short 

interval after the last Td; draft proposed recommendation. 

The rationale to recommend one dose of Tdap for health-care workers at short interval after the 

last dose of Td, rather than the General Recommendations’ ten-year interval, involves science, 

standard of care, and programmatic aspects.

Science. Data indicate substantial morbidity of adult pertussis, and health-care workers with 

direct patient contact are likely to be at increased risk. Tdap prevents pertussis in adults. The 

current standard of care supports Tdap vaccination of health-care workers because pertussis 

immune health-care workers will decrease exposures and secondary cases in both pediatric and 

adult-care settings. Tdap’s safety was demonstrated in a Canadian adolescent study that included 

intervals as short as 2 years after the last Td booster. However, no data indicate the duration of 

This document has been archived for historical purposes.
protection against pertussis in adults, or whether Tdap vaccination of health-care workers will be 

an effective strategy to prevent transmission. 

Standard of Care. The standard of care supports Tdap vaccination of health-care workers. ACIP 

already recommends worker vaccination to prevent the transmission of vaccine-preventable 

diseases in health-care settings, and ACIP already recommends that adults receive a single dose 

of Tdap to replace the next decennial Td. ACIP has also recommended that adults in contact with 

infants receive a Tdap dose at short interval after the last Td, to protect the adult from pertussis 

and to prevent transmission of pertussis to the infant 

Programmatic issues. Facility infrastructure readily allows implementation of a Tdap 

vaccination program for health-care workers, as done for other vaccines such as influenza. The 

costs of vaccination will be offset by reduction in infection control activities and medical leave, 

and by increasing vaccination rates. A single, simple ACIP recommendation can cover both 

pediatric and adult-care settings, and the health care workers can be prioritized for vaccination 

(e.g., according to infant- or direct patient contact). However, the vaccine will be an incremental 

increase in expenses for facilities that now offer Td to their staff, and a larger expense for those 

that do not. The necessary education and vaccination program will incur substantial cost, and the 

short interval from the last Td will increase implementation costs in the short term, since more 

health-care workers will be eligible for this vaccine than would be the case for a simple 

replacement for the next scheduled Td decennial booster. Finally, the guidelines for postexposure prophylaxis of vaccinated health-care workers will require review, as they were 

developed when adults were not vaccinated for pertussis. 

Proposed recommendation. The proposed text to recommend Tdap vaccination for health care 

workers was:

“Health-care workers who work in hospitals or ambulatory care settings and have direct 

patient contact should receive a single dose of Tdap as soon as feasible if they have not 

previously received Tdap. 

“Although Td is routinely recommended at intervals of 10 years, an interval as short as 2 

years from the last dose of Td is recommended for the Tdap dose among health-care 

workers (see recommendation for “Short Interval between Td and Tdap”). 

“These health-care workers include but are not limited to physicians, other primary care 

providers, nurses, aides, respiratory therapists, radiology technicians, medical and other 

students, dentists, social workers, chaplains, volunteers, dietary and clerical workers. 

“Other health-care workers (i.e., who do not work in hospitals or ambulatory care 

settings, or who do not have direct patient contact) should receive a single dose of Tdap 

according to the routine recommendation for use of Tdap among adults, if they have not 

previously received Tdap. 

“These workers are encouraged to receive the Tdap dose at an interval as short as 2 years 

from the last dose of Td (see recommendation, “Short Interval between Td and Tdap”). 

This document has been archived for historical purposes.
“Vaccinating health-care workers with Tdap will protect them against pertussis and is 

likely to reduce transmission to patients, other health-care workers, household members 

and persons in the community. 

“Priority should be given to vaccination of health-care workers who have direct contact 

with infants aged <12 months (see recommendation, “Prevention of Pertussis among 

Infants Aged <12 months by Vaccinating their Adult Contacts”) 

“Hospitals and ambulatory facilities are strongly encouraged to provide Tdap for healthcare workers and to use approaches that maximize vaccination rates, e.g., education about 

the benefits of vaccination, convenient access, and the provision of Tdap at no charge.* 

 

Discussion included: 

• Ms. Stinchfield suggested adding nursing students to the list. 

• Dr. Finger proposed saying that “... hospitals and ambulatory care facilities should 

provide ...” rather than “are strongly encouraged to..” 

• Dr. Gilsdorf suggested inserting text indicating the potential cost saving, to lower CEOs’ 

pain from the suggestion that the hospital pay for it. 

• The influenza statement provides a precedent for ACIP to say a facility “should” pay for 

the vaccine, even for populations that are not poor. The new HICPAC/ACIP health-care 

worker statement recommends that health-care workers’ recommended vaccines be 

purchased for them, as does OSHA’s requirement for health-care workers’ hepatitis B 

vaccine. Dr. Carolyn Bridges added that a recent California study demonstrated a strong 

association between having a vaccination paid for and its uptake by health-care workers.

Dr. Abramson summarized the general consensus to parallel the influenza statements’ 

recommendation that hospital and ambulatory care facilities “should provide,” rather 

than being “strongly encouraged to provide”, vaccination. Further discussion included: 

• Dr. Myers noted that this would leave out nursing homes, hospices, EMS services, etc. 

He suggested using the influenza guidelines terminology of “health care personnel” as a 

catch-all, rather than distinguishing between facilities. Dr. Murphy reported that as 

discussed by the Working Group, but rejected due to the scarcity of information on 

nursing homes. The nursing homes’ professional association also opposed it because of 

high turnover. She also reminded the committee that these health-care workers will be 

covered by the general adult Tdap recommendation. This wording was for catch-up 

pertussis vaccination of health-care workers in acute care facilities. Nonetheless, Dr. 

Myers advocated for ACIP’s boldness, as Dr. Poland had earlier, to further avoid 

potential deaths among the elderly. 

• Dr. Duchin asked if any studies are planned to better define understanding the vaccine’s 

efficacy in this setting. He was particularly interested since the ACIP has not 

recommended a change the current outbreak control and post-exposure prophylaxis 

protocols, which incur a significant cost to healthcare facilities. He also asked how 

transmission from unrecognized asymptomatic, or mildly symptomatic, health-care 

workers could be detected. Dr. Murphy responded that funding has been applied for to 

This document has been archived for historical purposes.
underwrite such studies. NIP would be glad to share its protocol with any facility, and 

greatly desires such data.

Dr. Allos moved to accept the recommendation with the edits discussed (i.e., saying “should 

provide” rather than “strongly encouraged to provide”, adding nursing students and 

ambulatory/acute care settings to the recommendation. 

When Dr. Murphy reported that the definition of “acute care setting” is variable between adult 

care physicians and pediatricians, Dr. Poland made a friendly amendment to define 

“ambulatory care settings” in a footnote. Ms. Stinchfield seconded that motion. 

Vote

To accept the proposed recommendation with edits.

In favor: Allos, Beck, Campbell, Finger, Gilsdorf, Hull, Lieu, Marcuse, Marcuse, 

Morita, Poland, Stinchfield, Womeodu, Abramson 

Opposed: None 

Abstained: None 

The motion passed. Dr. Murphy stated that the ACIP recommendation for health-care workers 

would be presented to HICPAC for a consensus statement. 

HERPES ZOSTER (SHINGLES) VACCINE

Storage/Handling of Herpes Zoster Vaccine

Presenter: Dr. Greg Wallace, NIP

Overview: Issues of cold storage for herpes zoster, varicella, LAIV, and combined 

measles, mumps, rubella, and varicella vaccine (MMRV)

The herpes zoster (HZ) vaccine up for licensure requires freezer storage. Three other current 

vaccines do so as well: varicella, proQuadTM (MMR-varicella) and live-attenuated influenza 

vaccine (LAIV). All must be stored at -15◦ C (5◦ F). Varicella can be stored at 2o-8o C for up to 

72 hours before reconstitution, as may LAIV for ≤60 hours before use. At room temperature, 

varicella holds its minimum potency of 1350 PFU for only 30 minutes after reconstitution. 

MMRV vaccine many not be stored at 2o-8o C for any period of time, and must be discarded after 

reconstitution if not used within 30 minutes. LAIV vaccine cannot be refrozen after thawing 

The requirement to store vaccines in the freezer leads to storage errors for both freezer-stored 

and refrigerator-stored vaccines. To determine if a freezer storage requirement poses a problem, 

CDC conducted two surveys of providers (>700) and practices (221). They found in both that 

17%-18% of freezers are too warm at any given time (Am J Prev Med 2002;23(4):246-253; 

Pediatrics 2001;107(6):3100-104). CDC’s guidelines advise turning the thermostat of standard 

household-type refrigerators to the coldest setting to maintain a -15o C temperature, but that 

could make the refrigerator too cold. Careful monitoring is needed. The refrigerator thermostat 

controls the volume of air going into the freezer, although freezers control their own 

temperature. Some refrigerators have temperature zones that vary. 

This document has been archived for historical purposes.
With freezer storage for some vaccines, the old dormitory-style refrigerators are no longer 

acceptable. About 30% of standard refrigerator freezers used to store varicella vaccine were too 

cold, and for inactivate vaccines, too-warm storage is less of a problem than too-cold storage. HZ 

vaccine users will include providers inexperienced in simultaneously maintaining vaccines in a 

refrigerator and a freezer. If they are not a VFC site, the lack of inspections will leave that 

uncorrected without a concerted education campaign by the Academies and the professional 

societies. 

Dr. Barbara Kuter, of Merck, reported their extensive education campaign when varicella 

vaccine was first released. That included putting information on the outside of the shipment box, 

on the vaccine vial itself, and additional information in the box. They plan the same activities for 

the zoster vaccine. Dr. Kelly Moore, of the Tennessee Immunization Program, reported their 

extensive experience with mishandled varicella vaccine that must be discarded yearly. They

recommend the small dorm-size, freestanding counter-high freezers, which cost ~$400-$500, to 

maintain the cold temperatures needed by varicella without compromising the refrigerated 

vaccines. 

Survey of Internists/Family Care Practitioners About Herpes Zoster Vaccine

Presenter: Dr. Allison Kempe, University of Colorado, Rocky Mountain Prevention 

Research Center

CDC and the Vaccine Policy Collaborative Initiative conducted a survey of internists and family 

care practitioners, randomly sampled to represent the ACP and AAFP national associations, as 

well as geographic regions, locations (urban, rural suburban), and setting (private practitioners, 

etc.). They were surveyed in two sentinel provider networks in November/December 2005, to 

determine:

 The perceived burden of Herpes Zoster (HZ) and Post-Herpetic Neuralgia (PHN) in 

primary care practice

 The practitioners’ intentions for recommending a new HZ vaccine if it is recommended 

by ACIP

 Perceived barriers to HZ vaccination.

The survey was administered over eight weeks by Internet or mail, based on the provider’s 

preference. The Internet and mail protocols were both described. The initial contact information 

included an informational paragraph about the clinical trial of the new herpes zoster vaccine 

(Oxman et al, NEJM 2005). The survey was pilot-tested in community advisory panel composed 

of internists and family medicine physicians from across country. 

The response rate was 62% (N=272) for general internal medicine (GIM) practitioners and 76% 

for those in family medicine (FM, N=328). Email surveys conducted by a Web-based survey 

company were selected by 66% of the respondents. FM and GIM characteristics did not differ 

appreciably, with ~80% in a private practice setting, although most family medicine physicians 

were in rural areas. Survey results were as follow for disease burden:

1. Number of zoster patients seen in the last year, with- and without PHN (combined 

GIM/FM data): without PHN, a median of 3 each for patients aged 50-59 and ≥60 years; 

and 1 and 2 patients, respectively, with PHN. Both groups were immunocompetent. 

This document has been archived for historical purposes.
2. Median visits to treat: 2 with PHN, 4 without; referred to sub-specialty: None, 74% 

without PHN, 36% with it; referred 1%-9% of patients: 22% and 41%; and referred 

≥10% of patients: 4 % and 23%, respectively. The specialties were ophthalmology 

(24%), dermatology (6%). Neurology (32%), and pain management (40%).

3. HZ and PHN cause significant burden of disease in my older patients: 35% strongly 

agreed; 46%, somewhat; 19% somewhat or strongly disagreed. 

Responses on vaccine use and recommending it were:

4. Vaccine use is warranted for the burden of HZ and its complications in patients. GIM: 

strongly agreed: 15% for those aged 50-59 years; 40% for those aged 60 to 79, 38% for 

>80; FM: 17% for age 50-59 years; 29% for 60-79 and 28% for >80. 

5. GIM likelihood to recommend HZ vaccination: ≥75% were very likely or somewhat 

likely for the two older groups and the severely debilitated; 76% were only somewhat 

likely or unlikely to vaccinate those 50-59 years old. 

6. Likelihood of FM to recommend HZ vaccination: The proportions of responses were 

similar to the GIM group, except they were more likely to recommend for the younger 

(50-59) age group, and their rate differences between likely and unlikely were less broad 

than the GIM group. 

Only 15% responded to an open-ended question about groups the physicians would consider offlabel use among. They listed patients overtly or functionally immunocompromised; those with 

chronic disease; those less able to tolerate shingles, or with shingles history, especially if severe; 

those who had varicella during infancy, immigrants; those who could infect others; healthy 

persons aged < 50 with varicella history; and healthy children and adults susceptible to varicella 

Barriers to vaccination were asked, according to definitely a barrier ─ somewhat of a barrier ─ 

not a barrier (N=595). Among the questions and responses were: 

• Reimbursement/financing issues: Definitely a barrier, GIM, 31%, FM: 44%, average 

38%; somewhat of a barrier, 38%; not a barrier, 24%. 

• Patients unwilling to pay if not covered: 37% - 43% - 20%. 

• Up front vaccine purchase costs: 30% - 35% - 35%.

• Patients will not think they need this: (23% - 45% - 33%. 

• Insufficient information about duration of protection: 22% - 40% -38% 

• Insufficient information about safety: 17% - 35% - 48% 

Barriers identified by <10% of providers included freezer storage; physician concern about 

safely administering a live attenuated virus to patients with chronic medical conditions; 

ineligibility of many patients if FDA retains the trials’ contraindicated groups; and 

contraindication for use among immunosuppressed patients. Others included unknown varicella 

disease status by patients not living in the U.S. for the past 30 years or foreign-born, and the 

potential for accidental vaccination of a child.

Summary of findings: 

• About 80% of FM and GIM providers strongly or somewhat agreed that HZ and PHN 

cause a significant disease burden in their older patients. 

• A significantly higher percentage of physicians strongly agreed to a higher burden for 

This document has been archived for historical purposes.
patients aged 60-79 years, versus 50-59 years, to sufficiently to warrant a vaccine (FM 

29% versus 17%; GIM 40% versus 15%). 

• Overall, both FM and GIM providers were very- or somewhat likely to recommend HZ 

vaccination for all age groups, but significantly more would do so for patients aged ≥60 

than those 50-59 years (FM 78% versus 60%, GIM 79% versus 57%). 

• The major perceived barriers to vaccination were financial (the top 3; inadequate 

reimbursement, up-front costs, patient unwillingness to pay), followed by patients not 

perceiving the need and insufficient information about duration of protection and safety. 

Shingles Prevention Trial, Zostavax®

Presenter: Dr. Paula Annunziato, Merck 

Overview: Epidemiology/medical need of HZ, severity and burden (medical and nonmedical) of disease; study population for ZOSTAVAX® and Shingles Prevention 

Studies; ongoing and planned activities. 

ZOSTAVAX® would be the first intervention to prevent HZ and its complications, including 

PHN. Its efficacy and safety was demonstrated in a pivotal study of participants aged >60 years. 

FDA is reviewing its license application now.

Herpes zoster epidemiology The increase of HZ incidence with advancing age was clearly 

charted by decade, with almost half (46%) occurring after age 60. PHN is the pain that persists 

after resolution of an HZ rash. It occurs in 10-20% of HZ patients, but in ≤30-50% of those aged 

>60. Estimated prevalence is ~500,000 cases in the U.S., with new incidence of 100-200,000 

annually. 

A study of pain severity (Katz J, Melzack R, Surg Clin N Amer 1999;79:231-52) was reported by 

patients with painful syndromes. The pain scores of zoster and PHN were exceeded only by 

those for abdominal hysterectomy and acute headache. HZ and PHN pain scores surpassed those 

for childbirth, fibromyalgia, chronic cancer and musculoskeletal pain. 

Disease burden. HZ causes 50-60,000 related hospitalizations annually (average stay of 5-7 

days) in the U.S., 12-15,000 of them with a primary HZ diagnosis. Yearly, about 3 million HZrelated ambulatory care visits occur, averaging 3 visits per episode, and 33% involve at least one 

visit to a specialist. But HZ patients with pain for ≥90 days have >10 visits on average. The nonmedical burden in the U.S. includes work and productivity loss, preliminarily estimated at an 

average of 3-7 days per HZ case. That equates to >600 to 750 thousand work days lost annually 

in the 50-59 year old category alone. Quality of life is severely affected in terms of physical, 

functional, social and psychological status. 

Zostavax® clinical development program. The Zostavax® clinical trial enrolled >20,000 

participants, mostly Caucasian, gender balanced and aged 30-99 years, with a variety of 

underlying medical conditions (except for altered immune status or past HZ history). The largest 

study in this program was the Shingles Prevention Study (SPS). 

This document has been archived for historical purposes.
Shingles Prevention Study (SPS). This was a double-blind, placebo-controlled, multi-center trial 

at 22 sites from November 1998 to April 2004. A collaboration between the VA, NIH, and 

Merck, it enrolled 38,546 subjects ≥60 years of age who were age-stratified (from 60-69 and ≥70 

years. Nine of ten subjects had ≥1 underlying medical condition. The subjects were randomized 

equally between ZOSTAVAX® or placebo. The ZOSTAVAX® was administered at its potency 

just prior to expiration, to ensure a conservative conclusion. Monthly telephone follow-up was 

done to identify HZ cases and to monitor adverse events (AE), and all subjects were actively 

contacted at the study’s end. 

The most frequently reported prior medical conditions were arthritis and hypertension, followed 

by a prostate disorder, allergic reaction, GI disorder, hypothyroidism and hypercholesterolemia. 

Many other conditions were also, but less frequently, reported. VE was assessed by HZ 

incidence, PHN incidence, and zoster pain burden. The latter combined the incidence, severity 

and duration of zoster-associated pain.

Results were as follow:

• Incidence of zoster, compared to placebo, was reduced by 51.3%; PHN incidence 

dropped by 66.5%, and zoster pain burden of illness dropped by 61.1%.. Interestingly, 

VE differed against HZ according to age strata, being higher in the younger 60-69 yearold age group (63%) versus those >70 (38%). VE against PHN and zoster pain burden of 

illness was similar between the two age groups. The greater VE for the younger age 

group appears to be from prevented HZ cases and their subsequent PHN and other 

complications. For the older age (>70) group, the vaccine benefits are HZ cases 

prevented and pain amelioration for breakthrough cases. 

• To assess VE among more frail persons, the subjects' baseline QALY scores related to 

functional limitations due to health status were assessed. About half the SPS subjects had 

at least some limitation in their functional status, defined among ~10% as moderate or 

severe. VE against HZ was well preserved in those groups, at ~50% among persons with 

self-rated mild, moderate, or severe limitation. The VE for PHN was similarly well 

preserved; the VE in these subgroups was ~60%, close to the 67% overall study VE. A 

similar ~60% VE against zoster pain burden of illness also was seen in these subgroups. 

• Duration of protection. The study subjects were followed for an average of 3.1 years 

(some for ≤5 years) to assess VE. The data showed it to be well preserved through year 

4, but data are still too few to be conclusive. However, a trend was apparent for high VE 

after the first year of vaccination: 62% for HZ, 85% for PHN, and 79% for herpes zoster 

burden of illness. The VE rises after year 1 to be very stable on all three end points. 

Safety. The ZOSTAVAX® safety data were built on the extensive VARIVAX® safety database 

of 56 million doses distributed since licensure in 1995. A clinical evaluation compared the 

>20,000 subjects vaccinated with ZOSTAVAX® to >19,000 placebo controls. The large cohort 

and trial database allows study power sufficient for even some uncommon adverse experiences 

(i.e., 97% power to detect events at 1.8 /10,000 frequency and 80% power to detect 0..8/10,000). 

Across eight Zostavax® studies to date, the vaccine has been well tolerated. 

• Adverse events reported in the SPS were recorded and assessed during the trial and in the 

safety follow-up period to day 42. SAEs were evenly distributed between the number and 

percentages of patients across the vaccination groups (i.e., 255 in the Zostavax® group, 

This document has been archived for historical purposes.
254 in the placebo group). An AE monitoring sub-study provided vaccine report cards 

for nonserious adverse experiences, which also were followed through the study for 

hospitalizations for any reason. That sub-study showed a difference in the number and 

percent of subjects who reported serious AEs (SAE), at 0.64 subjects in the Zostavax® 

group and 0.41 in the placebo group, which was statistically significant. But the reverse 

was also true, almost exactly, in the slight difference between the subjects who did not 

receive the vaccine report card, which balanced out the overall cohort. The Zostavax® 

group reported 191 SAEs and the placebo group reported 213. 

• The reported SAEs included five serious ones possibly related to vaccine: two in the 

Zostavax group (asthma exacerbation and a case of polymyalgia rheumatica) and three in 

the placebo group. Mortality was balanced between the two groups. The SAEs were 

listed by groups and were balanced overall. The most frequent was cardiovascular-related 

symptoms, at 0.4%, followed by general body- and central nervous system, and digestive 

systems, at 0.2%. For CVS, the smaller adverse event monitoring sub-study reports split, 

at 20 in the Zostavax® group and 12 subjects in the placebo group; for CNS, 12 in the 

Zostavax® and 6 in the placebo group. There was no clustering of similar events. 

SPS non-serious events included: 

• Local injection reactions were vastly higher in the Zostavax® group: at 48.3% versus 

16.6% in the placebo group, but that is not unexpected in such a vaccine study. Systemic 

AEs overall were well balanced between the two groups, although there was some 

elevation in events of vaccine-related headache episodes. These were fairly low in 

frequency but were statistically significant, at 1.4% in the Zostavax group and 0.9% 

percent in the placebo group. All other vaccine-related events, including hospitalizations 

and deaths, were balanced between the two groups 

• Inadvertent vaccination: There were no seronegative subjects found in the SPS. Two 

protocols looked specifically for this in adults; Zostavax® 003 and Varivax® 

• Rash. Since Varivax® carries a small vaccine-associated rash risk, that was explored for 

Zostavax.® Analysis determined the post-vaccination rash rate to be much lower than that 

for Varivax®, with ~0.3% of subjects reporting one to day 42 after vaccination. Of those, 

only two had lesions containing the vaccine Oka strain VZV. However, those two 

subjects were not from the SPS, but from earlier studies. No PCRs done in the SPS to 

detect herpes zoster identified the Oka strain of VZV.

Study 49. Even in the tropical counties where 003 was conducted, only 21 of 1000 screened 

were seronegative. Protocol 49 also was an international study, which found only 17 of 142 aged 

>30 who were varicella seronegative. So, no related safety issues were found upon vaccinating 

these subjects, but it is very rare to find them. 

Ongoing/Planned ZOSTAVAX® activities include the VA’s continuation of its durability of 

efficacy study among in SPS subjects (persistence sub-study in 12 of 22 sites that should go out 

to ten years). Placebo groups’ participants are being offered Zostavax® vaccination. Two 

clinical trials are ongoing; one a bridging study during the transition from frozen vaccine to a 

refrigerated formulation, and the other a study of concomitant administration of Zostavax® with 

inactivated influenza vaccine. 

This document has been archived for historical purposes.
In anticipation of licensure, a risk-management plan is in place to conduct postmarketing 

surveillance for adverse events, expand the already existing VZV identification program to allow 

PCR analysis of submitted clinical specimens, and expand the pregnancy registry to include 

subjects who received Zostavax.® 

Summary. The extensive ZOSTAVAX® clinical database includes >40,000 subjects enrolled in 

the clinical trail program, of whom >20,000 were vaccinated. The vaccine was shown to prevent 

HZ (VE=51%), PHN (VE=67%), and reduce HZ pain burden of illness (VE=61%). Zostavax® 

efficacy persists for four years postvaccination, to date; further data are hoped to be released 

soon to extend that outer range. The vaccine elicits a VZV-specific CMI response and has a an 

excellent safety profile

There was no discussion following this presentation. 

Public Comment.

Dr. Collette Curtis is an anesthesiologist at Emory University hospital who also works in pain 

management. She reported, of the many PHN patients seen, the particular debilitation among the 

elderly population. The pain has been described as like being burnt from within, and there is 

little that can be done for it. She recounted one story, to demonstrate how extreme the pain is, of 

a 70 year-old man who developed PHN in his thoracic dermatome. There were no openings to 

see him, until later that day, his son called demanding that he be seen, because he was at the 

kitchen table with a gun to his head, threatening to shoot himself. With our aging population, 

she expected to see many more developing PHN, and strongly supported vaccine development to 

prevent it. 

Dr. Harry Strothers is a family physician and geriatrician, and is on the faculty of Morehouse 

School of Medicine. He agreed with Dr. Curtis about the personal aspect of PHN. The great 

difficulty of this condition, as opposed to other pain syndromes, is that it does not respond well 

to pain medications, and the patients become quite desperate. Added to that is that many have 

other problems, such as being immunocompromised, which make them even more debilitated 

and less likely to leave their bed for physical therapy to keep them ambulatory. 

ACIP EVIDENCE BASED RECOMMENDATION CLASSIFICATIONS

Presenter: Dr. Daniel Fishbein, NIP 

Overview: Background and discussion of the process, major changes (already 

presented and new) 

The classifications of evidence on which to base ACIP recommendations have been in 

development since October 2003. Preliminary methods were first presented to the ACIP in 

February 2005, when the committee suggested that the evidence-based process be piloted on two 

ACIP recommendations. Continued work reviewed and adapted the evidence-based methods of 

the U.S. and Canadian Preventive Services Task Forces, the U.S. Task Force on Community 

Preventive Services, and the Oxford Centre for Evidence-Based Medicine.

This document has been archived for historical purposes.
ACIP vaccination recommendations are unique in their two major components, value to 

individuals and to community health. Although not every recommendation has community 

health implications (e.g., no transmissibility), both need to be clear when they are present. The 

pilot project has helped develop a method useful to modify the recommendations to five 

analytical steps for the ACIP process:

1. Develop an analytic framework. An analytic framework was outlined for the committee. 

Its steps were similar for both individual and public health, addressing vaccine usefulness, 

safety, effectiveness and efficaciousness, economic implications, and other vaccination 

considerations of an ACIP recommendation. For communities, the framework considers 

whether vaccinating a large number of individuals prevents transmission. The rabies 

vaccine recommendation was used as an example of one of a few recommendations that 

need not be evidence based. There are no non-ACIP dosage regimens and it is 

administered intradermally. That is not approved in the U.S., but the vaccine saves lives 

worldwide. The statement would have two components: prophylaxis with rabies vaccine 

for pre- and post-exposure, with five doses of vaccine and human rabies immune globulin 

in addition to wound cleansing. 

2. Search for and collect the evidence. The Working Group is searching for and collecting 

evidence through MEDLINE and the Cochrane library, bibliographies of relevant studies, 

and consultation with subject matter experts to find older or unpublished literature. 

Additional searches, data sources (e.g., VAERS) , or inclusion criteria are being specified 

by each vaccine working group. For rabies, a single study was found that used the ACIPapproved regimen, but for a vaccine no longer licensed in the U.S. (Wyeth’s human 

diploid cell rabies vaccine). They included studies of other biologics not currently U.S.-

licensed to gather efficacy and effectiveness data as an evidence base for rabies treatment.

The data scarcity forced the use of data on intermediate (elicit an antibody response) as 

well as final health outcomes. 

3. Evaluate the quality of the evidence. A level of evidence is being assigned based on the 

design of the study reviewed. The quality of study execution is assessed by examining 

six categories of potential threats to internal validity: the population and intervention 

description; the sampling done; exposure and outcome measurements; the data analysis; 

the interpretation of results; and others. A rating of “good” involves no or one study 

limitation; “fair” involves 2-4 limitations and “limited” involves more than 5 limitations. 

For rabies, a postexposure table was provided as an example, for the simple rabies nervetissue brain vaccine and for the human diploid cell vaccine. Determining the quality of 

the evidence and the magnitude of the effect was the most challenging aspect of the 

exercise, and the ACIP’s input was requested. The absence of community data was 

clearly represented by the one-armed (individual health effect) analytic framework for 

rabies vaccination. Additionally, there are almost no related economic data with which to 

calculate the cost effectiveness for the ACIP’s postexposure treatment advice. The 

Working Group is developing CE models for common scenarios faced by clinicians, with 

the help of Dr. Martin Meltzer, and a model will be created to calculate the benefit of the 

annual investment in rabies postexposure prophylaxis, despite multiple unknowns. 

This document has been archived for historical purposes.
4. Summarize the evidence. The evidence is summarized on separate tables for each key 

aspect of efficacy and effectiveness, safety, and economics. The quality of the aggregate 

evidence is determined by looking at (1) design hierarchy and (2) quality of execution for all

studies together. Finally the magnitude of effect is established by the combined outcomes and 

effect measures for all the reviewed studies. 

5. Convert the evidence into an overall recommendation. The Working Group plans to use 

four evidence groupings: 1) Immunization is not recommended for the target group; 2) consider 

individually recommendation; 3) immunization is not recommended for the target group; and 4) 

evidence is insufficient to make an overall recommendation. 

Several points in this process prompted vigorous discussion: 

• Again, for rabies: although pre-exposure prophylaxis is critical in the animal kingdom, it 

has little application for humans, and the human treatment has virtually no community 

health component. And the question became, with no final health-outcome studies using 

the ACIP-approved vaccine regimen, on what evidence basis can the ACIP vote?

• One considerations debated by the Working Group was whether vaccination should be 

provided for free, which studies show improve uptake. 

• Implementation of recommendations is already known to be difficult outside of the 

routine childhood vaccination schedule. Should the ability to implement be a 

consideration? Also in terms of implementation, what can a busy clinician do? They are 

already too busy to implement even a fraction of the most strongly recommended 

preventive services. 

• How are off-label recommendations to be handled in an evidence-based protocol (e.g., an 

ACIP recommendation for a narrower range of a target population)? Fitting that into the 

model is not easy, nor is the fit of permissive language. 

Next steps: The methods paper will be completed and presented at the June ACIP; the evidencebased rabies recommendation will be presented in June or October, and then followed by the 

evidence-based zoster recommendation. 

Discussion included: 

• Dr. Marcuse anticipated that the options (recommend; option; do not recommend; or no 

evidence base to be used) will ultimately require stratification as well. For example, 

would universal influenza immunization have equal weight to other recommendations, 

such as hepatitis B or measles?

• There is no set formula being developed to go from the design hierarchy and the quality 

of execution to a letter grade. Rather, the Working Group expects that the working group 

developing a statement/recommendation will suggest final recommendations, but the 

decision will still rest on the ACIP’s judgment.

• Mr. Beck asked what value there is for an economic analysis that finds no cost 

effectiveness, as defined by the measures used for a community program. Dr. Fishbein 

answered that, while many interventions in the Community Guide may be cost saving, 

there are others that are not cost saving but are still relatively cost effective in terms of 

quality adjusted life years. He offered to explain this further after the meeting. 

• Dr. Martin Myers wondered how this would affect the ACIP’s harmonized 

This document has been archived for historical purposes.
94/111

recommendations with its partner organizations. Dr. Marcuse found it to harmonize 

beautifully with the AAP’s evidence-based system and to be easily translatable. 

• Dr. Pickering asked how this analytic framework compared or fit to others in use, and 

how well the ACIP’s might be accepted by other organizations. Dr. Fishbein responded 

that the AHRQ is developing guidelines for the American College of Physicians to 

endorse the evidence-based recommendations of other organizations. Since the basis is 

evidence, there well could be some cross-endorsement. He was confident that this 

framework would fit the ACP’s needs. He also shared a chart of the USPSTF grading 

system to show its compatibility with the ACIP’s potential new system: 

• D

r. 

M

ar

ti

n 

M

y

er

s 

wondered how this would affect the ACIP’s harmonized recommendations with its 

partner organizations. Dr. Marcuse found it to harmonize beautifully with the AAP’s 

evidence-based system and to be easily translatable. 

Closing comments. 

With Dr. Abramson’s thanks and no further comment, the meeting was adjourned at 4:03 p.m. 

I hereby confirm that these minutes are accurate 

to the best of my knowledge.

__________________________________________ 

Jon Abramson, MD, Chair 

_______________________________ 

Date

USPSTF ACIP?

A Intervention strongly recommended } Immunization recommended B Intervention recommended

C No recommendation for or against 

intervention

Consider individually

D Intervention not routinely recommended Immunization not recommended

I Evidence insufficient to recommend for or 

against.

Evidence insufficient to make an 

overall recommendation

This document has been archived for historical purposes.
Attachment : Attendance

Name Organization

Dr. Shefer Abigail Centers for Disease Control and Prevention

Jon S. Abramson MD Wake Forest University School of Medicine

Kanowitz Adam Families Fighting Flu

Samuels Alicia MPH American Cancer Society

Rue Alison Centers for Disease Control and Prevention

Kanowitz Alissa Families Fighting Flu

Dr. Thierry Allavoine Sanofi Pasteur Msd

Jennifer Allen Merck & Co., Inc.

Ms. Friedman Allison MS Centers for Disease Control & Prevention

Dr. Kempe Allison MD, MPH University of Colorado Health Sciences Center

Ban Mishu Allos Vanderbilt University

Norma Allred CDCP NIP

Dr. Bandell Allyn Pharm.D. Medimmune

Dr. Cohn Amanda National Immunization Program

Mrs. Welsh Amanda GlaxoSmithKline

Miss Whatley Amanda MPH Centers for Disease Control and Prevention (Division of Global 

Migration and Quarantine)

Togba Amelia Personal

Ms. Parker Amy MSN, MPH Centers for Disease Control and Prevention

Pollack Amy E. MD, MPH Columbia University

Dr. Chevez Ana MD MPH Emory University

Dr. Chevez Ana E MD, MPH Emory University

Dr. Dayton Ana E. MD Constella Group

Mr. Padmanabhan Anant SG Cowen

Dr. Calugar Angela MD, MPH NIP/CDC

Ms. Makepeace Angelica RN, BSN St. Joseph''s Hospital of Atlanta

Ms. Isenhower Anne American Cancer Society

Dr. Schuchat Anne MD Centers for Disease Control and Prevention

Paula W. Annunziato M.D. Merck & Co., Inc.

Dr. Mounts Anthony M.D. Centers for Disease Control and Prevention

Mr. Wisniewski Anthony MedImmune, Inc.

This document has been archived for historical purposes.
William Atkinson National Immunization Program, CDC

James M Baggs Centers for Disease Control and Prevention

Carol J. Baker American Academy of Pediatrics

Dr. Jiang Baoming PhD CDC

Ms. Bardenheier Barbara MPH, MA CDC

Eliav Barr M.D. Merck Research Laboratories, Merck & Co., Inc.

Michelle Basket CDC

Dr. De Vos Beatrice MD GlaxoSmithKline Biologicals

Robert L. Beck Robert L. Beck: ACIP Voting Member

Sloat Ben MPH Georgia Division of Public Health

Dr. Schwartz Benjamin National Vaccine Program Office

Joan Benson MD, MPH Merck & Co., Inc.

Stuart Berman Centers for Disease Control and Prevention

Stevenson Beth MPH Centers for Disease Control and Prevention

Anderson Bethany National Immunization Program, CDC

Pollard Bette Centers for Disease Control and Prevention

Achal Bhatt CDC/NIP/ISD

Dr. Phelps Bill PhD American Cancer Society

Kaafee Billah MedImmune, Inc.

Gostout Bobbie MD Society of Gynecologic Oncologists

Andrew Bowser AB Writing and Editing, Inc. (media)

Damian Braga sanofi pasteur

Teresa Lynnette Brammer Centers for Disease Control and Prevention

Camp Brendan Centers for Disease Control and Prevention

Rutland Brent sanofi pasteur

Joseph Bresee Influenza Branch, CDC

Mr. Katzowitz Brian Children''s Healthcare of Atlanta

Dr. McAlvin Brian MD Emory University

Edward W Brink CDC/National Immunization Program/Program Operations Branch

Karen R. Broder National Immunization Program, CDC

Dennis Albert Brooks Merck & Co., Inc

Kristin Brown CDC-NIP (contractor through SAIC)

Dr. Gellin Bruce MD, MPH Department of Health and Human Services

Judith R. Campbell M.D. Advisory Committee on Immunization Practices

This document has been archived for historical purposes.
Scott Campbell CDC

Doug Campos-Outcalt American Academy of Family Physicians

Maria Victoria Cano Centers for Disease Control and Prevention

Mr. Garcia-Tunon Carlos Morgan Stanley

Ms. Henderson Caroline Emory University

Dr. Bridges Carolyn MD CDC

Dr. Deal Carolyn National Institutes of Allergy and Infectious Diseases, NIH

Dr. Runowicz Carolyn MD University of Connecticut Health Center

Christine Casey Centers for Disease Control and Prevents

Dr. Hanlon Cathleen VMD CDC

rupprecht charles cdc

Thompson Charlis CDC/NIP

James E. Cheek Indian Health Service

Ana Elena Chevez Emory University

Bo-Hyun Cho National Immunization Program

Dr. Coffey Chris MD Ross Clinic

Dr. Shibutani Chris MD JPMorgan - Healthcare Research

Gause Christine PhD Merck & Co., Inc.

Miss Stephen Clarencia MedImmune, Inc.

vellozzi claudia md, mph cdc/nip

Dr. Lewin Clement Acambis

Stephen L. Cochi Centers for Disease Control and Prevention

Kathleen Coelingh MedImmune Vaccines

Dr. curtis colette M.D. Emory University Hospital

Estivariz Concepcion MD National Immunization Program, Centers for Disease Control and 

Prevention

Lenore Cooney Cooney Waters

Nancy J. Cox Centers for Disease Control and Prevention

Mr. Heit Craig Cooney/Waters Group

Suhr Cristen MPH Centers for Disease Control (Contractor)

George Tams Curlin National Institutes of Health

Dr. Jorgensen Cynthia DrPH CDC

Miss Knighton Cynthia Centers for Disesase Control and Prevention

Mr. Babcock Dale National Immunization Program

This document has been archived for historical purposes.
Dr. Morse Dale MD, MS New York State Department of Health

Dr. Guris Dalya MD, MPH CDC

Mr. Braga Damian Sanofi pasteur

Dr. Gordon Daniel MD Sanofi Pasteur Inc

Dr. Payne Daniel PhD Centers for Disease Control

Natalie J. Darling CDC

Dr. Salisbury David CB Department of Health

Dr. Schofield David Pharm D GlaxoSmithKline

Jill Davila CDC - LHI

Xiaohong Davis CDC/DVRD/Influenza

Anna DeBlois Association of State and Territorial Health Officials

Shelley Deeks Public Health Agency of Canada

Dr. Kruzikas Denise PhD GlaxoSmithKline

Penelope H. Dennehy M.D. American Academy of Pediatrics

Ms. Gaffoglio Diane Nancy Lee & Associates

Dr. Simpson Diane MD, PhD National Immunization Program

Dr. CAMPENS Dirk GLAXOSMITHKLINE BIOLOGICALS

Mr. Dalrymple Donald "Dack" Dalrymple & Associates, LLC

Humphrey-Franklin Donelle Public Health

Dr. Rickert Donna DrPH Centers for Disease Control

Jag Dosanjh GlaxoSmithKline

Mr. Kilgus Duane Centers for Disease Control and Prevention

Gary Dubin GlaxoSmithKline Biologicals

Eileen Dunne CDC

Mr. Gwozda Ed GlaxoSmithKline

Reed Eddie MD DCPC, NCCDPHP, CoCHP, CDC

Dr. Yamada Eileen Immunization Branch, California Department of Health Services

Dr. Perry Elaine MD Merck and Co., Inc.

Elbasha Elamin Merck & Co., Inc

Goss Elizabeth Ropes & Gray

Unger Elizabeth PhD, MD Centers for Disease Control and Prevention

Mr. Weintraub Eric CDC/OCSO/ISO

Dasbach Erik PhD Merck Research Laboratories

Grau Erik sanofi pasteur

This document has been archived for historical purposes.
Burns Erin Influenza Branch, Centers for Disease Control and Prevention

Ms. Joseph Eugenia parents

Gary L. Euler Centers for Disease Control and Prevention

Geoffrey Evans M.D. National Vaccine Injury Compensation Program, Health Resources 

and Services Administration

James Everette Evans Sound On-Site, Inc.

Dr. Soud Fatma PhD, RN Immunization Safety Office

Mark B. Feinberg MD, PhD Merck & Co., Inc.

Mr. Han Feng Henry Schein, Inc

Reginald Finger ACIP member (no affiliation)

Daniel B. Fishbein CDC

Amanda Foley GlaxoSmithKline

Stephen M. Ford Military Vaccine Agency

Stephan L Foster Pharm.D. ACIP Liaison Representative - APhA

Dr. Lebel Francois MedImmune Inc.

Dr. Malinoski Frank MedImmune, Inc.

Dr. Clark Fred PhD The Children''s Hospital of Philadelphia

Mr. Wyand Fred American Social Health Association

Leonard R Friedland GlaxoSmithKline

Miss Sylvina Frutos GlaxoSmithKline

Jeffrey Fu PhD Merck & Co., Inc.

Dr. Xu Fujie MD, PhD Centers for Disease Control and Prevention

Stanley A. Gall M.D. The American College of Obstetricians and Gynecologists

Sandra Gambescia Centers for Disease Control and Prevention

Demetria Gardner Centers for Disease Control and Prevention

Paul M. Gargiullo Centers for Disease Control and Prevention; National 

Immunization Program; Epidemiology and Surv eillance Division

Mr. Stein Gary Families Fighting Flu

Diana Gaskins BSN, MSN Division of Public Health, Georgia Immunization Program

Mr. Porges Geoff PhD Sanford C. Bernstein

Dr. Garnett Geoffrey PhD Imperial College London

Dr. Porges Geoffrey Sanford Bernstein

Jeff George M.D. New York,

Jeffrey George TDG Inc.

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Peter Georges MD Brown Medical School

Ruth Gilmore Georgia Immunization Program

Janet R. Gilsdorf University of Michigan

Dr. Mootrey Gina DO, MPH Centers for Disease Control and Prevention

Roger Glass CDC

John W. Glasser Centers for Disease Control and Prevention

JIll Gordon-Evans Sound On-Site, Inc.

Michelle G. Goveia Merck Research Laboratories, Merck & Co., Inc.

Jesse Earl Greene South Carolina Department of Health and Environmental Control

Amy Groom Indian Health Service

Dr. Herrera Guillermo MD, MBA CDC

Jill G. Hackell Wyeth

Neal Arthur Halsey Johns Hopkins University

Danielle Halstrom GlaxoSmithKline

Claire Hannan Association of Immunization Managers

Mr. Chesson Harrell PhD Centers for Disease Control and Prevention

Dr. Strothers Harry MD, MMM Morehouse School of Medicine

Richard M. Haupt M.D. Merck & Co., Inc.

Penny M. Heaton Merck Research Laboratories

Dr. Baggett Henry MD, MPH Centers for Disease Control and Prevention

Teresa M. Hesley Merck & Co., Inc.

Beth F. Hibbs CDC OD OSCO ISO

Mark Hirth Merck & Co., Inc

Barbara J Howe GlaxoSmithKline

Dr. BOGAERTS Hugues GLAXOSMITHKLINE BIOLOGICALS

Dr. Harry Hull Minnesota Department of Health

Harry Frazer Hull Minnesota Department of Health (member ACIP)

Gina Hunt Merck & Co., Inc.

Dr. Jevaji Indira MD Health Resourses and Services Adminstration

Bruce L. Innis M.D GlaxoSmithKline

Dr. Chan Ivan Merck Research Labs

Dr. Alexander James Jr. CDC

Kelly James Goldman Sachs

Dr. Pellissier James Merck Research Laboratories

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Ransom James NACCHO

Mr. Singleton James National Immunization Program, CDC

Mr. Harrison James R. MAPA CDC/CCID/National Immunization Program

Ms. Agosti Jan MD Bill & Melinda Gates Foundation

Dr. Gidudu-Nsubuga Jane MD,MPH Immunization Safety Office, Office of the Chief Science 

Officer,CDC

Ms. Quinn Jane GlaxoSmithKline

Dr. Seward Jane MBBS, MPH CDC

Dr. Zucker Jane MD, MSc New York City Department of Health and Mental Hygiene

Ms. Skidmore Janet Merck & Co., Inc.

Shirley Jankelevich South Carolina Department of Health and Environmental Service

Dr. Hong Jason PhD Sanford C. Bernstein

Mr. Schwartz Jason MBE University of Pennsylvania Center for Bioethics

Bauman Jay MedImmune, Inc.

Mr. Hackman Jeff MedImmune, Inc.

Dr. Chodakewitz Jeffrey MD Merck & Co.

Dr. Cooper Jeffrey MD Cooper Pediatrics, PC

Dr. Duchin Jeffrey MD Public Health Seattle & King County

Dr. Silber Jeffrey Merck & Co., Inc.

Mr. Stoddard Jeffrey MD MedImmune, Inc.

Ms. Huntington Jennifer Emergent BioSolutions

Mrs. Lastinger Jennifer Families Fighting Flu

Tai Jennifer MD Vanderbilt University School of Medicine

Ms. White Jennifer Ketchum

Ms. Zavolinsky Jennifer MHS, CHES Every Child By Two

Mr. Shelton Jerry RPh Merck Vaccine Division

Mr. Blanton Jesse MPH Centers for Disease Control and Prevention

Ms. Leung Jessica National Immunization Program

Ms. Xi Jian GlaxoSmithKline

Hackell Jill MD Wyeth Vaccines Research

Dr. Buffington Joanna Centers for Disease Control and Prevention

Kearney Joanne Solvay Pharmaceuticals

Mr. Lastinger Joe Families Fighting Flu

Dr. Modlin John MD Dartmouth Medical School

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Mr. Vittas John Families Fighting Flu, Inc.

Dr. Douglas, Jr. John M. MD Centers for Disease Control and Prevention, National Center of 

HIV, STD & TB Prevention, Divison of STD Prevention

David Rue Johnson MD, MPH sanofi pasteur

Tanya A. Johnson Oak Ridge Institute for Science and Technology 

(ORISE)/CDC/National Immunization Program (NIP)

Mary Suzanne Johnson-DeLeon Centers for Disease Control and Prevention

Dr. Bocchini, Jr. Joseph M.D. American Academy of Pediatrics

Dr. Heyse Joseph Merck Research Laboratories

Mr. Sullivan Joseph Merck & Company, Inc.

M. Patricia Joyce M.D. Centers for Disease Control

Mrs. Magner Judith GlaxoSmithKline Pharmaceuticals

Miss Rusk Judith Infectious Diseases in Children and Infectious Disease News

Dr. Shindman Judith sanofi pasteur Limited

Dr. Schmidt Judy EdD CDC NIP EIPB

Ms. Gee Julianne Centers for Disease Control and Prevention

Ms. Schafer Julie MPH, MS Office of the Secretary, Department of Health and Human Services

Laurie Kamimoto CDC

Ms. Mason Karen MPA National Immunization Program

Mrs. Townsend Karen RN Georgia Chapter American Academy of Pediatrics

Ms. Sapsis Kari MPH National Immunization Program-CDC

Mr. Iqbal Kashif NIP/CDC

Dr. Poehling Katherine MD, MPH Vanderbilt University Medical Center

Dr. Neuzil Kathleen MD,MPH PATH

Ms. Harbour (Felton) Kathryn Centers for Disease Control and Prevention

Dr. Kohl Katrin MD, PhD, MPH Centers for Disease Control and Prevention

Mark Katz Centers for Disease Control and Prevention

Samuel Lawrence Katz Infectious Diseases Society of America

Mrs. Dougherty Kelley Merck & Co., Inc.

Ms. Green Kahn Kelly MPA American Cancer Society

Conzen Kendra CDC Div Global Migration and Quarantine

Mr. Bart Kenneth MD, MPH, MSHPM Department of Health and Human Services, National Vaccine 

Program Office

Mr. Dennison Kenneth Wyeth Pharmaceuticals

Dr. Schmader Kenneth Duke University/Durham VA Medical Centers

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Dr. Ault Kevin MD Emory University School of Medicine

Dr. Hazelwood Kimberley Pharm D Public Heatlh

Dr. workowski kimberly md centers for disease control and prevention

Maureen Kolasa Centers for Disease Control

Katrina Kretsinger National Immunization Program, CDC

Armendariz Kris Society of Gynecologic Oncologists

Mrs. Charlotte Kroft GlaxoSmithKline

Barbara J. Kuter Ph.D., MPH Merck & Co., Inc.

Dr. Anderson Larry MD DVRD, NCID, CDC

Philip S. LaRussa Columbia University

Ms. Leidel Laura Centers for Disease Control and Prevention/Office of 

Director/Immunization Safety Office

Miss Richardson Laura Influenza Branch-CDC

Mrs. Johnson Laurie Centers for Disease Control and Prevention

Len Lavenda sanofi pasteur

Herschel W. Lawson Centers for Disease Control and Prevention

Charles W. LeBaron NIP

Dr. Bennett LEE SANOFI PASTEUR MSD

Marie-Michele Leger American Academy of Physician Assistants

Laura Leidel Centers for Disease Control and Prevention

Ms. Cooney Lenore C Cooney/Waters Group

Roland A. Levandowski M.D. National Institutes of Health

Tracy Lieu Harvard Pilgrim Health Care and Harvard Medical School

Anna M. Likos Centers for Disease Control and Prevention

Dr. Alexander Linda PhD Digene Corporation

Ms. Russell Lola CDC, OD Media Relations

Mr. Thomas Lonnie Henry Schein Incorporated

Adriana Lopez MHS Centers for Disease Control and Prevention

Dr. Gavin Loretta MPH, PhD Division of Reproductive Health, CDC

Suchita A. Lorick CDC/NIP/ISD

Douglas R. Lowy M.D National Cancer Institute, National Institutes of Health

Beverly J. Lybrand Merck & Company, Inc.

Ms. Bahta Lynn RN Minnesota Department of Health

McIntyre Lynne Centers for Disease Control and Prevention

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Dr. Otten Mac MD CDC, NIP

Andrew Macknight GlaxoSmithKline

Susan Patricia Malone Coastal Health District 9-1

Dr. Patel Manisha MD Centers for Disease Control and Prevention

Susan E. Manning CDC

Edgar K. Marcuse MD, MPH Children''s Hospital and Regional Medical Center

Cortese Margaret CDC

Ms. McGlynn Margaret Merck & Co., Inc.

Watkins Margaret CDC

Ms. Murray Marie SoWrite

Lauri Markowitz Centers for Disease Control and Prevention

Tanner Wilson Marsha Society of Gynecologic Oncologists

Ms. Doroshenk Mary MA American Cancer Society

Mrs. Eiken Mary Society of Gynecologic Oncologists

Ms. Mulholland Mary National Immunization Program

Dr. Staat Mary M.D., MPH Associate Professor of Pediatrics, Cincinnati Children''s Hospital 

Medical Cente

Dr. Lindegren Mary Lou MD CDC

Christopher Mast Merck Research Laboratories

Eric Edward Mast Centers for Disease Control and Prevention

Dr. Esona Mathew Ph.D CCID/Centers for Disease Control and Prevention

Mr. Garrett Matt Wyeth Vaccines

Mr. David Matthew MD Independent

Hogben Matthew PhD Centers for Disease Control and Prevention

Dr. Ciarlet Max Merck & Co., Inc.

Dr. El Sherif May MD Centers for Disease Control and Prevention

Mary McCauley National Immunization Program

William Paul McKinney University of Louisville School of Public Health and Information 

Sciences

Lindley Megan MPH National Immunization Program/ Centers for Disease Control & 

Prevention

Wharton Melinda National Immunization Program, CDC

Ms. Arvay Melissa CDC

Miss Habel Melissa CDC, Division of STDP, BIRB

Lynne Mercedes Georgia Division of Public Health

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Dr. Decker Michael sanofi pasteur

McNeil Michael MD CDC

Dr. Pride Michael PhD Wyeth Research

Tidwell Michelle RN, BSN Georgia Chapter American Academy of Pediatrics

Amy B. Middleman MD, MPH, MS Ed Baylor College of Medicine

Christina M. Mijalski Centers for Disease Control, National Immunization Program

Elaine R. Miller Centers for Disease Control and Prevention (CDC)

Tucker Miriam E. Pediatric News

Ann Moen Centers for Disease Control

Ms. Gaul Moira MPH Family Research Council

Dr. Marin Mona MD CDC

Dr. Saraiya Mona MD, MPH CDC

Martha C. Monroe Centers for Disease Control

Kelly Lynn Moore MD, MPH Tennessee Department of Health

John S. Moran Centers for Disease Control and Prevention

Julie Morita Chicago Department of Public Health

Dale Morsr M.D. New York State Department of Health

Linda S. Murphy Centers for Medicare & Medicaid Services

Trudy Murphy Centers for Disease Control and Prevention

Martin G. Myers National Network for Immmunization Information

Dr. Cox Nancy PhD Centers for Disease Control and Prevention

Ms. Fasano Nancy National Immunization Program CDC

Ms. Roach Nancy n/a

Mrs. Stoback Nanette sanofi pasteur

Ms. Revzina Natalya MD Centers for Disease Control and Prevention

Dr. Monika Naus on behalf of Public Health Agency of Canada; British Columbia 

Centre for Disease Control

Mr. Agran Neal Sanford Bernstein

Deb Neivert MedImmune

Thomas M. Netzer Merck & Co., Inc.

Kristin Lee Nichol Department of Veterans Affairs Medical Center

Dr. Liddon Nicole Centers for Disease Control and Prevention

Karen H Nielsen GlaxoSmithKline

Ms. Dahill Noreen GlaxoSmithKline

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Dr. Baylor Norman Ph.D. Food and Drug Administration

Glen Nowak Centers for Disease Control and Prevention

Dennis J. O''Mara Immunization Services Division, National Immunization Program, 

CDC

M. Carolyn O''Mara Centers for Disease Control and Prevention, Health Marketing, 

Creative Services

Paul Allan Offit MD The Children''s Hospital of Philadelphia

Peter R. Paradiso Wyeth

Umesh Parashar CDC

Smith Parker Parker Smith Photography

Mr. BAROLLIER Pascal GlaxoSmithKline

Wortley Pascale CDC

Manisha Patel CDC, NIP

Dr. Offit Paul MD The Children''s Hospital of Philadelphia

Mrs. Rose Paula GlaxoSmithKline Pharmaceuticals

Christine Pearson Centers for Disease Control and Prevention

Michele Pearson Centers for Disease Control and Prevention

Dr. Nuorti Pekka MD, DSc Centers for Disease Control and Prevention

Haber Penina MPH CDC

Mrs. Heaton Penny MD Merck & Co., Inc.

Mr. Sprigg Peter Family Research Council

Diane C. Peterson Immunization Action Coalition

Mr. Hosbach Philip sanofi pasteur

Dr. MONTEYNE Philippe MD, PhD GlaxoSmithKline Biologicals S.A.

Ms. Arthur Phyllis Merck & Co Inc

Larry K. Pickering Centers for Disease Control and Prevention

Cheng Po-Yung Ph.D. CDC/NCID/DVRD/I/ES

Gregory A. Poland Mayo Clinic and Foundation

Alicia Postema CDC/CCID/NCID/DVRD/Influenza

Keith R. Powell American Academy of Pediatrics, Committee on Infectious 

Diseases

Dr. Kutty Preeta MD, MPH Centers for Disease Control and Prevention

Dr. Eidex Rachel PhD Centers for Disease Control and Prevention

Mrs. Hlay Rachel GlaxoSmithKline

Aaron Thomas Rak CDC, NIP, ISD

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Dr. Strikas Raymond M.D. National Immunization Program

Ms. Werth Rebecca GlaxoSmithKline

Dr. Turcios Reina Centers for Disease Control and Prevention

Dr. Jenkins Renee R. MD Howard University

Margaret Rennels GlaxoSmithKline

Margaret B Rennels GlaxoSmithKline

Mr. Dinovitz Richard Wyeth Pharmaceuticals

Dr. Dixon Richard M.D. Centers for Disease Control and Prevention; NCHM; DPPP

Dr. Franka Richard PhD. Centers for Disease Control and Prevention

Kanowitz Richard Families Fighting Flu

Dr. Salmon Richard DO Children''s Healthcare of Atlanta at Scottish Rite

Mr. Nelson Rick National Immunization Program/CDC

Donna Rickert Centers for Disease Control and Prevention

Dr. Helfand Rita CDC

Dr. Itzler Robbin PhD Merck Research Laboratories

Mr. Morlend Robert Centers for Disease Control

Mr. Oliver Robert Wyeth Pharmaceuticals

Perry Robert M.D. Centers for Disease Control and Prevention

Dr. Steinbrook Robert M.D. New England Journal of Medicine

Mr. Cuca Roberto JP Morgan

Dr. Womeodu Robin MD Methodist University Hospital

Lance E. Rodewald M.D. National Immunization Program, CDC

Von Roebuck Centers for Disease Control and Prevention

Dr. bernier roger phd nip

Dr. Levandowski Roland MD National Insitutes of Health, National Insititue of Allergy and 

Infectious Diseases

Dr. Rodriguez Romeo CENSIA (SS)

Mr. Hibshoosh Ron Goldman Sachs JBWere

Mr. Van Duyne Ron Immunization Information Systems, NIP, CDC

Ms. Dhara Rosaline MA.,MPH CDC

Dr. Tiernan Rosemary MD, MPH Division of Vaccines, Center for Biologics, FDA

Sandra W. Roush CDC/NIP/ESD

Beth Rowe-West DPH-DHHS-NC Immunization Branch

Dr. Patricia Saddier MD, PhD Merck Research Laboratories

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Turner Sam Ropes & Gray

Dr. Katz Samuel MD Duke University Medical Center

Dr. Dos Santos Chaves Sandra MD Centers for Disease Control and Prevention

Tammy A. Santibanez National Immunization Program

Dr. Jeanne M. Santoli MD, MPH CDC NIP

Ms. Landry Sarah GlaxoSmithKline

Ms. Spurgeon Sarah New England Healthcare Institute

Mona Saraiya CDC

Debbie Saslow PhD American Cancer Society

Carlos Sattler M.D. Merck & Co., Inc.

William Schaffner MD Chairman, Department of Preventive Medicine, Vanderbilt 

University School of Medicine

Florian Schodel M.D Merck Research Laboratories

Anne Schuchat Centers for Disease Control and Prevention

Dr. Schmid Scott PhD Centers for Disease Control and Prevention

Ms. Shapowal Sharon GlaxoSmithKline Pharmaceuticals

Kate M. Shaw CDC

David K Shay CDC

Dr. Leader Shelah PhD Medimmune

Tom Shimabukuro CDC/NIP

Alan J. Sievert M.D., M.P.H. American Academy of Pediatrics-Georgia Chapter

Dr. Staprans Silvija PhD Emory University Vaccine Center

Thomas W. Skinner CDC

Eric T. Skjeveland Merck Vaccine Division

Barbara A. Slade M.D. Centers for Disease Control

Ianthia Smith Kaiser Permanente

Dr. Jean Clare Smith Medical Officer, Assistant to the Director for Immunization Policy, 

NIP, CDC

Nicole Michelle Smith Centers for Disease Control and Prevention/Influenza Branch

Pamela Srivastava Centers for Disease Control

Ms. Hoffman Stacey Centers for Disease Control

Dr. Plotkin Stanley MD Sanofi Pasteur

Ms. Steele Stefanie CDC

Renna Stephanie National Immunization Program

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Dr. Cochi Stephen MD Centers for Disease Control and Prevention

Mr. Yoo Steve Sanford Bernstein

Dr. Gordon Steven MD Cleveland Clinic Foundation

Dr. Rosenthal Steven MD FDA/CBER

Mr. Vignau Steven Merck & Co., Inc.

Patricia (Patsy) Stinchfield CPNP Children''s Hospitals and Clinics of Minnesota

Shannon Stokley Centers for Disease Control and Prevention

Raymond A. Strikas M.D. CDC NIP

Stacy Stuerke Merck Vaccine Division

Mrs. Crosby Susan Women In Government

Ms. Garfield Susan Digene Corporation

Dr. Lett Susan MD MA Dept Public Health

Dr. Reef Susan MD CDC, NIP

Ms. Van Aacken Susan National Immunization Program

Ms. Watkins Susan Sanofi pasteur

Ms. Matter Susanna Leerink Swann

Ms. LAW Suzette Centers for Disease Control and Prevention

Dr. Gregg Sylvester Merck & Co., Inc.

Litjen (L.J) Tan American Medical Association

Ms. Malik Tasneem CDC/National Immunization Program

Jonathan L. Temte MD/PhD American Academy of Family Physicians

Ms. Rutledge Teresa BA Centers for Disease Control and Prevention

Andrew Kroger Thaddeus Centers for Disease Control and Prevention

Dr. Allavoine Thierry SANOFI PASTEUR MSD

Dr. Uyeki Tim MD, MPH, MPP Centers for Disease Control and Prevention

Mr. Wang Tim UBS Securities

Mr. Obara Timothy GlaxoSmithKline

Tejpratap S. P. Tiwari MD Centers for Disease Control and Prevention

Dr. Shimabukuro Tom MD, MPH, MBA CDC/NIP

John Treanor University of Rochester

Monica Trigg Georgia Immunization Program

Ms. Watson Tureka L. McKing Consulting Corporation

James C. Turner MD American College Health Association

James P. Tursi M.D. GSK Biologicals

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Mr. Jodhpurkar Uday Sanofipasteur

Elizabeth R. Unger Centers for Disease Control and Prevention

Thomas M. Vernon MD Consultant to Vaccine Companies

Dr. Benard Vicki CDC

Peter Vigliarolo Cooney Waters Group

Mr. Ahonkhai Vincent M.D. GlaxoSmithKline Pharmaceuticals

Charles Vitek CDC (National Center for HIV, STD, and TB Prevention)

Cara Vivarelli-O''Neill Merck & Co., Inc

Mr. Garrett W. Matthew Wyeth

Gregory S. Wallace Centers for Disease Control and Prevention

Teresa R. Wallis Centers for Disease Control and Prevention

Dr. Orenstein Walter MD Emory University

Elisabeth A. Ward Georgia Division of Public Health

Barbara May Watson Division of Disease Control, Immunization Program, The 

Philadelphia Department of Public Health

Dr. Hachey Wayne DO, MPH Department of Defense

Donna L. Weaver National Immunization Program, CDC

David Webster Webster Consulting Group

Bruce G. Weniger MD CDC

Deborah L. Wexler MD Immunization Action Coalition

Mark Alan Whitaker M.D. America''s Health Plans

Marc -Alain Widdowson Centers for Disease Control and Prevention

Eddie L. Wilder CDC, NID, ISD

Dr. Thompson William PhD OCSO/Immunization Safety Office

Dr. Vecino William MD MKGNY

Amy Wishner PA Chapter, American Academy of Pediatrics

Charles (Skip) Wolfe National Immunization Program

Eileen L Yee (Lau) Centers for Disease Control and Prevention

Elizabeth York GlaxoSmithKline

Laura Jean York Wyeth

Dr. Moore Zack MD Emory University

John M. Zahradnik sanofi pasteur

Fangjun Zhou NIP

This document has been archived for historical purposes.